Indoline derivatives and method for using and producing the same

ABSTRACT

The present invention relates to a compound of the formula: where n, R and R are those defined herein. The present invention also relates to use of a compound of Formula 1 in treating a clinical condition associated with fibrotic disorder.

FIELD OF THE INVENTION

The present invention relates to a compound of the formula:

where n, R1 and R2 are those defined herein. The present invention alsorelates to use of a compound of Formula 1 in treating a clinicalcondition associated with fibrotic disorder.

BACKGROUND OF THE INVENTION

Fibrotic disorders affect many organ systems, including heart, bloodvessels, kidney, liver and lung. An estimated 45% of deaths in theUnited States are attributed to disorders that are characterized byvarying degrees of fibrosis. This alarming statistic is oftenunderappreciated since the ‘cause of death’ is often end-stage organfailure, although in many cases organ failure is attributed toprogressive fibrosis.

The most severe and deadly fibrotic lung disease is idiopathic pulmonaryfibrosis (IPF), characterized by progressive scar tissue formation andirreversible destruction of the lung parenchyma, resulting ingas-exchange abnormalities and ultimately respiratory failure. IPF iswidely regarded as a disease of aging, as it disproportionately affectsthe elderly population with a mean age of 66 years at the time ofdiagnosis. IPF is associated with high morbidity and mortality with amedian survival rate of less than three years. Further, the survivalrate of IPF patients markedly decreases with age.

Although two drugs have recently gained FDA-approval for IPF, no drugtreatment has been shown to definitively improve quality of life orsurvival for IPF patients. The current drugs only moderately slow theprogression of lung decline. There are no available therapies that can‘reverse’ fibrosis.

Therefore, there is a clear need for more effective treatments for IPFand other fibrotic diseases in order to improve the patient experienceand outcomes.

SUMMARY OF THE INVENTION

some aspects of the invention are based on the discovery by the presentinventors that the reactive oxygen species (ROS)-generating enzyme,NADPH oxidase (Nox4), is a critical mediator of myofibroblast functionsand validation of its role in animal models of lung fibrosis. Nox4expression is elevated in the lungs of patients with IPF and in IPF lungfibroblasts.

Since this discovery by the present invention, Nox4 has been implicatedin a variety of fibrotic diseases including the kidney, liver, skin, andheart. More recently, the present inventors have developed a novel aginganimal model of persistent lung fibrosis. This model more accuratelyrecapitulates the persistent nature of IPF and offers a more clinicallyrelevant efficacy testing protocol, where reversal of establishedfibrosis can be evaluated. Using this model, the present inventors havedemonstrated that, in the context of aging, lung injury leads to theacquisition of a senescent and apoptosis-resistant myofibroblastphenotype, which impairs fibrosis resolution. Without being bound by anytheory, it is believed that this myofibroblast phenotype is mediated bya redox imbalance associated with sustained activation of Nox4. Further,genetic/pharmacologic targeting of Nox4 led to the reversal ofage-associated persistent fibrosis and increased survival.

Currently, there are no selective Nox4 inhibitors clinically available.One particular aspect of the invention provides is highly selective Nox4inhibitor compounds. Another aspect of the invention provides a methodfor using a compound of the invention for treating a subject sufferingfrom a clinical condition associated with fibrotic disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing (A) H₂O₂ inhibition by compounds in HEK cellsstably transferred to overexpress Nox4 evaluated by Amplex Red assay;and (B) IC₅₀ evaluated for UANox048 in HEK cells stably transfected tooverexpress Nox4.

FIG. 2 is a graph showing UANox048 scavenger activity for H₂O₂ assessedby (A) Amplex Red assay. (B) ROS-Glo assay, and (C) cellular viabilityin HEK cells stably transfected to overexpress Nox4 treated withUANox048.

FIG. 3 is a graph showing UANox048 evaluated for (A) Nox1 selectivity byAmplex Red assay, (B) Nox2 selectivity by Amplex Red assay, and (C)Xanthine Oxidase selectivity by Amplex Red assay.

FIG. 4 is a graph showing H₂O₂ inhibition by Amplex Red assay of humanlung fibroblasts (IMR90 cells) treated with UANox034, UANox008, UANox019and UANox048.

FIG. 5 is a graph showing Western-immunoblotting (A) and densitometricanalyses (B) of αSMA in human lung fibroblasts (IMR90 cells) treatedwith UANox048.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein the term “optionally substituted” means one or moresubstituents may or may not be present. In addition, as is well known toone skilled in the art, the term “substituent” refers to a group otherthan hydrogen. For example, the term “optionally substituted” means thatthe referenced chemical structure is unsubstituted or contains at leastone substituent selected from the list consisting of halogen, cyano,C₁₋₆alkyl, C₁₋₄alkenyl, C₁₋₆alkynyl, C₁₋₆haloalkyl, —O—₁₋₆alkyl,—O—C₁₋₆alkenyl, —O—C₁₋₆alkynyl, —0— C₁₋₆haloalkyl, phenyl, -phenyl-OMe,-phenyl-CF₃, C₁₋₆alkyl-fluorophenyl, pyridyl, —O—phenyl,—C₁₋₆alkyl-phenyl, —O—C₁₋₆alkyl-phenyl, —O-pyridyl-CF₃,haloalkyl-substituted —O— pyridyl, pyrimidinyl, —OH, —OMe, —NH₂,—N(H)Me, —NHC(O)Me, —C(O)NEt₂, —SH, —S(O)₂— piperidinyl,—S(O)₂-phenyl-CF₃, —S(O)₂-phenyl-OCF₃, —S(O)₂-fluorophenyl, —S(O)₂NMe₂,—S(O)₂NEt₂ and —SMe.

“Alkyl” refers to a saturated linear monovalent hydrocarbon moiety ofone to twelve, typically one to six, carbon atoms or a saturatedbranched monovalent hydrocarbon moiety of three to twelve, typicallythree to sic, carbon atoms. Exemplary alkyl group include, but are notlimited to, methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, andthe like.

“Alkylene” refers to a saturated linear saturated divalent hydrocarbonmoiety of one to twelve, typically one to six, carbon atoms or abranched saturated divalent hydrocarbon moiety of three to twelve,typically three to six, carbon atoms. Exemplary alkylene groups include,but are not limited to, methylene, ethylene, propylene, butylene,pentylene, and the like.

“Aryl” refers to a monovalent mono-, bi- or tricyclic aromatichydrocarbon moiety of 6 to 15 ring atoms which is optionally substitutedwith one or more substituents. When substituted, the aryl group istypically substituted with one, two or three substituents within thering structure. When two or more substituents are present in an arylgroup, each substituent is independently selected. When substituted,typical substituents for the aryl group include, but are not limited to,alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, halo, nitro, cyano,cycloalkyl, optionally substituted phenyl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, or optionallysubstituted aryl. More specifically the term aryl includes, but is notlimited to, optionally substituted phenyl, optionally substituted1-naphthyl, and optionally substituted 2-naphthyl, etc.

“Aralkyl” refers to a moiety of the formula —R^(a1)R_(a2) where R^(a1)is an alkylene group and R^(a2) is an optionally substituted aryl groupas defined herein. Exemplary aralkyl groups include, but are not limitedto, benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylphenyl, and thelike.

“Cycloalkyl” refers to a non-aromatic, monovalent mono- or bicyclichydrocarbon moiety of three to ten ring carbons. The cycloalkyl can beoptionally substituted with one or more substituents. when substituted,cycloalkyl typically has one, two, or thee substituents within the ringstructure, where each substituent is independently selected. Cycloalkylcan also include one or ore non-aromatic unsaturated double bond withinthe ring structure. However, the term “saturated” is used as a prefix,then no multiple (e.g., double or triple) bond is present within thecycloalkyl ring structure. Suitable substituents for cycloalkyl include,but not limited to, exemplary substituents listed above for an arylgroup.

“Cycloalkylalkyl” refers to a moiety of the formula —R^(b1)R^(b2) whereR^(b1) is an alkylene group and R^(b2) is an optionally substitutedcycloalkyl group as defined herein. Exemplary cycloalkylalkyl groupsinclude, but are not limited to, cyclopropylmethyl, cyclohexylpropyl,3-cyclohexyl-2-methylpropyl, and the like.

The terms “halo,” “halogen”and “halide” are used interchangeably hereinand refer to fluoro, chloro, bromo, or iodo.

“Haloalkyl” refers to an alkyl group as defined herein in which one ormore hydrogen atom is replaced by same or different halo atoms. The term“haloalkyl” also includes perhalogenated alkyl groups in which all alkylhydrogen atoms are replaced by halogen atoms. Exemplary haloalkyl groupsinclude, but are not limited to, —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, andthe like.

The term “heteroaryl” means a monovalent monocyclic or bicyclic aromaticmoiety of 5 to 12 ring atoms containing one, two, three or four ringheteroatoms selected from N, O, or S, the remaining ring atoms being C.The heteroaryl ring can optionally be substituted with one or moresubstituents. When substituted, typically heteroaryl has one, two orthree substituents, each of which is independently selected. Exemplarysubstituents for heteroaryl include those listed above for aryl group.Exemplary heteroaryl groups include, but are not limited to, pyridyl,furanyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl,isoxazolyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzofuranyl,isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl,benzimidazolyl, benzisoxazolyl, benzothiophenyl, dibenzofuran,benzodiazepin-2-one-5-yl, and the like.

The terms “heterocyclyl” and “heterocycloalkyl” are used interchangeablyherein and refer to a non-aromatic monocyclic moiety of three to eightring atoms in which one or two ring atoms are heteroatoms selected fromN, O, or S(O)_(n) (where n is an integer from 0 to 2), the remainingring atoms being C, where one or two C atoms can optionally be acarbonyl group. the heterocyclyl ring can be optionally substitutedindependently with one or more substituents. When substituted,heterocycloalkyl typically has one, two or three substituents, each ofwhich is independently selected. Heterocycloalkyl can include one ormore non-aromatic double bonds within the ring structure. However, theterm “saturated” is used as a prefix, then no multiple (e.g., double ortriple) bond is present within the heterocycloalkyl ring structure.Suitable substituents for heterocycloalkyl include, but not limited to,exemplary substituents listed above for an aryl group.

“Leaving group” has the meaning conventionally associated with it insynthetic organic chemistry, i.e., an atom or a group capable of beingdisplaced by a nucleophile and includes halo (such as chloro, bromo, andiodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g.,acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g, 2,4-dinitrophenoxy), methoxy,N,O-dimethylhydroxylamino, and the like.

“Pharmaceutically acceptable excipient” refers to an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use.

“Pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desired pharmalogicalactivity of the parent compound. Such salts include: (1) acid additionsalts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike, or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,(3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2,2,2]-oct-2-ene-1carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion, or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

The terms “pro-drug” and “prodrug” are used interchangeably herein andrefer to any compound which releases an active parent drug according toFormula I in vivo when such prodrug is administered to a mammaliansubject. Prodrugs of a compound of Formula I are prepared by modifyingone or more functional group(s) present in the compound of Formula I insuch a way that the modification(s) may be cleaved in vivo to releasethe parent compound. Prodrugs include compounds of Formula I wherein ahydroxy, amino, or sulfhydryl group in a compound of Formula I is bondedto any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugsinclude, but are not limited to, esters (e.g., acetate, formate, andbenzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) ofhydroxy functional groups in compounds of Formula I, and the like.

“Protecting group” refers to a moiety, except alkyl groups, that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting group can be found in T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)edition, John Wiley & sons, New York, 1999, and Harrison and Harrison etal., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley andSons, 1971-1996), which are incorporated herein by reference in theirentirety. Representative hydroxy protecting groups include acyl groups,benzyl and trityl ethers, tetrahydropyranyl ethers, trialkysilyl ethersand ally ethers. Representative amino protecting groups include, formyl,acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ),tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), and the like.

“Corresponding protecting group” means an appropriate protecting groupcorresponding to the heteroatoms (i.e., N, O, P or S) to which it isattached.

“A therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

“Treating” or “treatment” of a disease includes: (1) preventing thedisease, i.e., causing the clinical symptoms of the disease not todevelop in a mammal that may be exposed to or predisposed to the diseasebut does not yet experience of display symptoms of the disease; (2)inhibiting the diseases, i.e., arresting or reducing the development ofthe disease or its clinical symptoms; or (3) relieving the disease,i.e., causing regression of the disease or its clinical symptoms.

As used herein, the term “treating”, “contacting” or “reacting” whenreferring to a chemical reaction means adding or mixing two or morereagents under appropriate conditions to produce the indicated and/orthe desired product. It should be appreciated that the reaction whichproduces the indicated and/or the desired product may not necessarilyresult directly from the combination of two reagents which wereinitially added, i.e., there may be one or more intermediates which areproduced in the mixture which ultimately leads to the formation of theindicated and/or the desired product.

As used herein, the terms “those defined above” and “those definedherein” when referring to a variable incorporates by reference the broaddefinition of the variable as well as any and all of the more narrowerdefinitions, if any.

Compounds of the Invention:

One aspect of the invention provides a compound of the formula:

wherein

-   -   n is an integer from 0 to 4;    -   each R¹ is independently selected from the group consisting of        alkyl, haloalkyl, halogen, nitro, heterocycloalkyl, cycloalkyl,        optionally substituted heteroaryl, optionally substituted aryl,        and —OR^(a), where each R^(a) is independently selected from the        group consisting of hydrogen, alkyl, heteroaryl, aryl and        cycloalkyl; or    -   two adjacent R¹ together with carbon atoms to which they are        attached to form heterocycloalkyl;    -   R² is selected from the group consisting of:        -   (a) a moiety of the formula:

-   -   (b) a moiety of the formula:

-   -   (c) an optionally substituted aryl; and    -   (d) an optionally substituted heterocycloalkyl,    -   wherein    -   m is 1 or 2,    -   X¹ is optionally substituted heterocycloalkyl, —NR⁴R⁵,        —NR^(b)SO₂R⁶, —NR^(b)C(O)R⁶, —NR^(b)SO₂NR⁴R⁵, or —NR^(b)CONR⁴R⁵;    -   X² is O, NR^(c) or S;    -   R³ and R^(3′) are each independently hydrogen or alkyl;    -   each of R⁴ and R⁵ is independently hydrogen or alkyl, or R⁴ and        R⁵ together with the nitrogen atom to which they are attached to        form an optionally substituted heterocycloalkyl;    -   each of R^(b) and R^(c) is independently hydrogen or alkyl; and    -   R⁶ is —N(R^(d))₂, optionally substituted aryl, optionally        substituted heteroaryl or optionally substituted heterocyclyl;    -   provided that the compound is not:    -   N-(N,N-diethylaminosulfonyl)-2-(indolin-1yl)propane-1amine);    -   1,1-diethyl-3-(2-(indolin-1-yl)ethyl)urea;    -   (N-(N,N-dimethylaminosulfonyl)-2-(indolin-1-yl)ethane-1-amine);    -   4-(2-(indolin-1-yl)ethyl)morpholine;    -   1-(2-(piperidin-1-yl)ethyl)indoline;    -   N-(2-(indolin-1-yl)propyl)morpholine-4-sulfonamide;    -   N-(2-(indolin-1-yl)propyl)piperidine-1-sulfonamide;    -   4-fluoro-N-(2-(indolin-1-yl)propyl)benzenesulfonamide;    -   4-fluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide;    -   N-(2-(indolin-1-yl)ethyl)-4-methoxybenzenesulfonamide;    -   3,4-difluoro-N-(2-(indolin-1-yl)propyl)benzenesulfonamide;    -   N-(2-indolin-1-yl)propyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide;    -   N-(2-(indolin-1-yl)ethyl)benzo[d][1,3]dioxole-5-sulfonamide;    -   N-(2-(indolin-1-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide;    -   N,N-diethyl-4-(2-(indolin-1-yl)-2-oxoethyl)piperazine-1-sulfonamide;    -   1-(indolin-1-yl)-2-(4-(morpholinosulfonyl)piperazin-1-yl)ethan-1-one;    -   1-(indolin-1-yl)-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethan-1-one;    -   4-(3-(indolin-1-yl)-3-oxopropyl)-N,N-dimethylpiperazine-1-sulfonamide;    -   N,N-diethyl-4-(3-(indolin-1-yl)-3-oxopropyl)piperazine-1-sulfonamide;    -   1-(indolin-1-yl)-3-(4-(morpholinosulfonyl)piperazin-1-yl)propan-1-one;    -   1-(indolin-1-yl)-3-(4-(pyrimidin-2-yl)piperazin-1-yl)propan-1-one;    -   2-(cycloheptylamino)-1-(indolin-1-yl)ethan-1-one; or    -   3-(cycloheptylamino)-1-(indolin-1yl)propan-1-one.

One aspect of the invention provides a compound of the formula:

wherein

-   -   n is an integer from 0 to 4;    -   each R¹ is independently selected from the group consisting of        alkyl, halogen, nitro, heterocycloalkyl, cycloalkyl, optionally        substituted heteroaryl, optionally substituted aryl, and        —OR^(a), where each R^(a) is independently selected from the        group consisting of hydrogen, alkyl, heteroaryl, aryl and        cycloalkyl;    -   or two adjacent R¹ together with carbon atoms to which they are        attached to form heterocycloalkyl;    -   R² is        -   (a) a moiety of the formula:

-   -   (b) a moiety of the formula:

-   -   (c) an optionally substituted aryl; or    -   (d) an optionally substituted heterocycloalkyl, wherein        -   m is 1 or 2,        -   X¹ is optionally substituted heterocycloalkyl, —NR⁴R⁵,            —NR^(b)SO₂R⁶, —NR^(b)(C(O)R⁶, —NR^(b)SO₂NR⁴R⁵, or            —NR^(b)CONR⁴R⁵;        -   X² is O, NR^(c) or S;        -   R³ is hydrogen or alkyl, typically R³ is hydrogen or methyl;        -   each of R⁴ and R⁵ is independently hydrogen or alkyl,        -   alternatively, R⁴ and R⁵ together with the nitrogen atom to            which they are attached to form an optionally substituted            heterocycloalkyl,        -   each of R^(b) and R^(c) is independently hydrogen or alkyl;            and        -   R⁶ is optionally substituted aryl, optionally substituted            heteroaryl.

Within the Compound of Formula I, when R² is a moiety of the formula:

and m is 1, and R³ is —CH₃, and X¹ is —NHSO₂NR⁴R⁵, then R⁴ and R⁵ bothare not ethyl.

In one embodiment, m is 1. Yet in another embodiment, m is 2.

Still in another embodiment, R² is a moiety of the formula:

where m, X¹ and R³ are those defined herein.

Yet in other embodiments R⁴ and R⁵ are independently selected from thegroup consisting of methyl and ethyl. Still in other embodiments, R⁴ andR⁵ together with the nitrogen atom to which they are attached to form aheterocycloalkyl of the formula:

where

-   -   X³ is O or —NR⁷; and    -   R⁷ is alkyl, heteroaryl, or —SO₂NR⁸R⁹,    -   wherein    -   each of R⁸ and R⁹ is independently selected from alkyl, or R⁸        and R⁹ together with the nitrogen atom to which they are        attached to form an optionally substituted heteroaryl or        optionally substituted heterocycloalkyl.

Within these embodiments, in some instances X³ is —NR⁷, where R⁷ is asdefined herein. In some particular cases, R⁷ is methyl, ethyl,optionally substituted pyramid-2-yl, optionally substitutedmorpholin-4-yl or optionally substituted piperidin-1-yl.

Yet in other embodiments, X² is O.

In other embodiments, R² is optionally substituted aryl. In someparticular embodiments, R² is phenyl that is optionally substituted withalkyl haloalkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, —NR⁴R⁵,—NR^(b)SO₂R⁶, —NR^(b)C(O)R⁶, —NR^(b)SO₂NR⁴R⁵, or —NR^(b)CONR⁴R⁵, whereR^(b), R⁴, R⁵ and R⁶ are those defined herein.

Still in other embodiments, R² is optionally substitutedheterocycloalkyl. In some instances, R² is an optionally substitutedpiperidin-3-yl. Yet in other instances, piperidin-3-yl is optionallysubstituted with alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl.

In some embodiment, n is 1.

Yet in other embodiments, R¹ is alkyl, haloalkyl, alkoxy, optionallysubstituted phenyl optionally substituted pyrazolyl, optionallysubstituted pyridinyl, or optionally substituted pyrimidinyl, or two ofR¹ groups adjacent to one another together with carbon atoms to whichthey are attached to form heterocycloalkyl. Some of the specificexamples of R¹ include those selected from the group consisting ofmethyl, trifluoromethyl, methoxy, 4-fluorophenyl,4-(trifluoromethyl)phenyl, 4-nitrophenyl, 4-(N,N-dimethylamino)phenyl,4-methoxyphenyl, 3-methoxyphenyl, 1-methyl-1H-pyrazol-4-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, andbenzo[d][1,3]dioxol-5-yl. Still in other examples include where n is 2and two R¹ groups are adjacent to one another together form a moiety ofthe formula —O[CH₂]_(k)O—, where k is 1 or 2.

In some embodiments,

-   -   n is 0 or 1;    -   R¹ is optionally substituted aryl;    -   X¹ is —NR⁴R⁵, —NR^(b)C(O)R⁶, —NR^(b)SO₂NR⁵R⁵ or —NR^(b)SO₂R⁶;    -   R³ is hydrogen or alkyl;    -   each of R⁴ and R⁵ is independently hydrogen or alkyl.    -   or R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form an optionally substituted heterocycloalkyl;    -   R^(b) is hydrogen or alkyl; and    -   R⁶ is optionally substituted aryl or optionally substituted        heterocyclyl.

In some embodiments,

-   -   X¹ is —NR⁴R⁵, —NHC(O)R⁶, —NHSO₂NR⁴R⁵ or —NHSO₂R⁶;    -   R³ is hydrogen or methyl;    -   R⁴ and R⁵ are alkyl,    -   or R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form an optionally substituted piperazine ring; and    -   R⁶ is optionally substituted phenyl or optionally substituted        pyrolidinyl.

In some embodiments,

-   -   X¹ is —NR⁴R⁵, —NHC(O)R⁶, —NHSO₂NR⁴R⁵ or —NHSO₂R⁶;    -   R³ is hydrogen or methyl;    -   R⁴ and R⁵ are ethyl,    -   or R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form an optionally substituted piperazine ring; and    -   R⁶ is optionally substituted phenyl or optionally substituted        pyrolidinyl.

In some embodiments,

-   -   n is 1;    -   R¹ is 3-methoxyphenyl; and    -   R⁴ and R⁵ are ethyl.

In some embodiments,

-   -   n is 0;    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form piperazine ring substituted with R⁷, wherein R⁷        is alkyl —SO₂R¹² or —SO₂NR⁸R⁹,    -   wherein        -   R⁸ and R⁹ are alkyl,        -   R¹² is optionally substituted aryl; and    -   R⁵ is phenyl or pyrolidinyl, wherein the phenyl is substituted        with one or more of halogen, haloalkyl, —O-haloalkyl,        —O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl, cyano,        -4-methoxyphenyl.

In some embodiments, R³ is hydrogen.

In some embodiments, R³ is alkyl.

In some embodiments, R³ is methyl.

Some of the representative compounds of the invention are provided inTables 1-4 below:

TABLE 1 Structures of NOX4 inhibitors

Compound R¹ R² R³ 1 (UANOX001) H

H 2 (UANOX002) H

H 3 (UANOX003) H

H 4 (UANOX004) H

H 5 (UANOX011) H

H 6 (UANOX012) H

H 7 (UANOX021) H

H 8 (UANOX013) H

H 9 (UANOX017) H

H 10 (UANOX018) H

H 11 (UANOX006) CH₃

H 12 (UANOX007) CH₃

H 13 (UANOX008) CH₃

H 14 (UANOX019) CH₃

H 15 (UANOX010) CH₃

H 16 (UANOX020) CH₃

H 17 (UANOX009) CH₃

H 18 (UANOX033) CH₃

H 19 (UANOX034) CH₃

H 20 (UANOX035) CH₃

H 21 (UANOX037) CH₃

H 22 (UANOX036) CH₃

23 CH₃

24 CH₃

25 CH₃

26 CH₃

27 CH₃

28 (RC_02_54) CH₃

29 CH₃

30 CH₃

31 CH₃

32 (UANOX049) CH₃

H 33 (UANOX051) H

H 34 (UANOX050) H

H 35 (UANOX048) CH₃

H 36 (UANOX055) CH₃

H 37 (UANOX056) CH₃

H 38 (UANOX054) CH₃

H 39 CH₃

H 40 (UANOX072) CH₃

H 41 CH₃

H 42 (UANOX069) CH₃

H 43 CH₃

H 44 CH₃

H 45 (UANOX070) CH₃

H UANOX075 H

UANOX076 H

UANOX077 H

UANOX078 H

UANOX079 H

UANOX080 H

UANOX081 H

TABLE 2 Structures of NOX4 inhibitors

Compound n R⁸ 46 (UANOX028) 1

47 (UANOX025) 1

48 (UANOX026) 1

49 (UANOX027) 1

50 (RC_01_92) 1

51 (UANOX032) 2

52 (UANOX029) 2

53 (UANOX030) 2

54 (UANOX031) 2

55 (UANOX022) 2

TABLE 3 Representative Compounds of the Invention

Compound n R⁹ 56 1

57 2

TABLE 4 Representative Compounds of the Invention

Compound R¹⁰ 58 (UANOX038)

59

60

61

62

63

64

65

66

67

TABLE 5 Representative Compounds of the Invention

Compound R¹¹ 68

69

70

71

72

73

74

75

76

77

TABLE 6 Structures of NOX4 inhibitors

Compound R¹¹ 78

79

80

81 (UANOX062)

82

83

84

85

86

87

88

89

90 (UANOX063)

91 (UANOX066)

92 (UANOX067)

In some embodiments, the compound is

Compound Number Compound Structure Compound Name UANOX001

N-(N,N-diethylaminosulfonyl)-2- (indolin-1-yl)ethane-1-amine UANOX002

1,1-diethyl-3-(2-(indolin-1- yl)ethyl)urea UANOX003

N-(N,N-dimethylaminosulfonoyl)-2- (indolin-1-yl)ethane-1-amine UANOX004

N-(2-(indolin-1-yl)ethyl)pyrrolidine- 1-sulfonamide UANOX006

1,1-diethyl-3-(2-(indolin-1- yl)propyl)urea UANOX007

N-(N,N-dimethylaminosulfonyl)-2- (indolin-1-yl)propane-1-amine UANOX008

N-(2-(indolin-1- yl)propyl)pyrrolidine-1-sulfanamide UANOX009

N-(2-(indolin-1-yl)propyl)piperidine- 1-sulfonamide UANOX0UAN10

N-(2-(indolin-1- yl)propyl)morpholine-4-sulfonamide UANOX011

N-(2-(indolin-1-yl)ethyl)-4- methylpiperazine-1-carboxamide UANOX012

N-(2-(indolin-1-yl)ethyl)morpholine- 4-sulfonamide UANOX013

N-(2-(indolin-1-yl)ethyl)piperidine-1 sulfonamide UANOX017

4-(2-(indolin-1-yl)ethyl)morpholine UANOX018

1-(2-(piperidin-1-yl)ethyl)indoline UANOX019

N-(2-(indolin-1-yl)propyl)-4- methylpiperazine-1-carboxamide UANOX020

N-(2-(indolin-1- yl)propyl)pyrrolidine-1-carboxamide UANOX021

N-(2-(indolin-1-yl)ethyl)pyrrolidine- 1-carboxamide UANOX0192

1-(indolin-1-yl)-2-(4-(pyrimidin-2- yl)piperazin-1-yl)ethan-1-oneUANOX022

1-(indolin-1-yl)-3-(4-(pyrimidin-2- yl)piperazin-1-yl)propan-1-oneUANOX023

2-(cycloheptylamino)-1-(indolin-1- yl)ethan-1-one UANOX024

3-(cycloheptylamino)-1-(indolin-1- yl)propan-1-one UANOX025

N,N-diethyl-4-(2-(indolin-1-yl)-2- oxoethyl)piperazine-1-sulfonamideUANOX026

1-(indolin-1-yl)-2-(4- (morpholinosulfonyl)piperazin-1- yl)ethan-1-oneUANOX027

1-(indolin-1-yl)-2-(4-(piperidin-1-ylsulfonyl)piperazin-1-yl)ethan-1-one UANOX028

4-(2-(indolin-1-yl)-2-oxoethyl)-N,N- dimethylpiperazine-1-sulfonamideUANOX029

N,N-diethyl-4-(3-(indolin-1-yl)-3- oxopropyl)piperazine-1-sulfonamideUANOX030

1-(indolin-1-yl)-3-(4- (morpholinosulfonyl)piperazin-1- yl)propan-1-oneUANOX031

1-(indolin-1-yl)-3-(4-(piperidin-1- ylsulfonyl)piperazin-1-yl)propan-1-one UANOX032

4-(3-(indolin-1-yl)-3-oxopropyl)- N,N-dimethylpiperazine-1- sulfonamideUANOX033

N-(2-(indolin-1-yl)propyl)-2- (pyridin-4-yl)thiazole-4-carboxamideUANOX034

N-(2-(indolin-1-yl)propyl)-4- methoxybenzenesulfonamide UANOX035

4-fluoro-N-(2-(indolin-1- yl)propyl)benzenesulfonamide UANOX036

N-(2-(5-(3-methoxyphenyl)indolin-1- yl)propyl)-N,N-diethyl-1-sulfonamideUANOX037

N-(2-indolin-1-yl)propyl)-4- methylpiperazine-1-sulfonamide UANOX0254

N-(2-(5-(3-methoxyphenyl)indolin-1- yl)propyl)-4-methylpiperazine-1-sulfonamide UANOX038

N-(N,N-diethylaminosulfonyl)-4- (indolin-1-yl)-phenyl-1-amine UANOX048

N-(2-indolin-1-yl)propyl)-4- (trifluoromethyl)benzenesulfonamideUANOX049

N-(2-(indolin-1-yl)propyl)-4- (trifluoromethoxy)benzenesulfonamideUANOX050

N-(2-(indolin-1-yl)ethyl)-4- methoxybenzenesulfonamide UANOX051

N-(2-(indolin-1-yl)ethyl)-4- fluorobenzene)sulfonamide UANOX054

N-(2-(indolin-1-yl)propyl)-2-(4- methoxyphenyl)thiazole-4- carboxamideUANOX055

N-(2-(indolin-1-yl)propyl)-2- phenylthiazole-4-carboxamide UANOX056

N-(2-(indolin-1-yl)propyl)-2-(4- (trifluoromethyl)phenyl)thiazole-4-carboxamide UANOX062

1-(2-(4-((4- (trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl)indoline UANOX063

N,N-diethyl-4-(2-(indolin-1- yl)ethyl)piperazine-1-sulfonamide UANOX064

1-(2-(4-((4- fluorophenyl)sulfonyl)piperazin-1- yl)ethyl)indolineUANOX066

N,N-diethyl-4-(2-(indolin-1- yl)ethyl)piperazine-1-carboxamide UANOX067

1-(2-(4-(2-fluorobenzyl)piperazine-1- yl)ethyl)indoline UANOX069

N-(2-(indolin-1-yl)propyl)-2,3- dihydrobenzo[b][1,4]dioxine-6-sulfonamide UANOX070

N-(2-(indolin-1-yl)propyl)-4-((5- (trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide UANOX071

N-(2-(indolin-1-yl)propyl)-4- phenoxybenzenesulfonamide UANOX072

3,4-difluoro-N-(2-(indolin-1- yl)propyl)benzenesulfonamide UANOX073

4-cyano-N-(2-indolin-1- yl)propyl)benzenesulfonamide UANOX075

N-(2-indolin-1-yl)ethyl)-4- (trifluoromethyl)benzenesulfonamide UANOX076

N-(2-indolin-1-yl)ethyl)-4- (trifluoromethoxy)benzenesulfonamideUANOX077

N-(2-(indolin-1- yl)ethyl)benzo[d][1,3]dioxole-5- sulfonamide UANOX078

N-(2-indolin-1-yl)ethyl)-2,3- dihydrobenzo[b][1,4]dioxine-6- sulfonamideUANOX079

N-(2-indolin-1-yl)ethyl)-4- phenoxybenzenesulfonamide UANOX080

N-(2-indolin-1-yl)ethyl)-4-((5- (trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide UANOX081

3,4-difluoro-N-(2-(indolin-1- yl)ethyl)benzenesulfonamide UANOX082

4-cyano-N-(2-(indolin-1- yl)ethyl)benzenesulfonamide UANOX083

N-(N,N-diethylaminosulfonyl)-2- (indolin-1-yl)-2-methylpropane-1- amineUANOX084

N-(2-indolin-1-yl)-2-methylpropyl)- 4-(trifluoromethyl)benzenesulfonamide UANOX085

N-(2-indolin-1-yl)-2-methylpropyl)- 4-phenoxybenzenesulfonamide UANOX086

4-fluoro-N-(2-(indolin-1-yl)-2- methylpropyl)benzenesulfonamide UANOX087

3,4-difluoro-N-(2-indolin-1-yl)-2- methylpropyl)benzenesulfonamideUANOX088

N-(2-indolin-1-yl)-2-methylpropyl)- 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide UANOX089

N-(2-indolin-1-yl)-2-methylpropyl)- 4-(methoxy)benzenesulfonamideUANOX090

N-(2-indolin-1-yl)-2-methylpropyl)- 4-(trifluoromethyl)benzenesulfonamide

In some embodiments, the invention provide compounds of the formula

-   -   wherein    -   n is 0 or 1;    -   R¹ is optionally substituted aryl;    -   X¹ is —NR⁴R⁵, —NR^(b)C(O)R⁶, —NR^(b)SO₂NR⁴R⁵ or —NR^(b)SO₂R⁶;    -   R³ and R^(3′) are each independently hydrogen or alkyl;    -   each of R⁴ and R⁵ is independently hydrogen or alkyl,    -   or R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form an optionally substituted heterocycloalkyl;    -   R^(b) is hydrogen or alkyl; and    -   R⁶ is optionally substituted aryl or optionally substituted        heterocyclyl.

In some embodiments, the compounds are of formula (Ia), wherein X¹ is—NR⁴R⁵, —NHC(O)R⁶, —NHSO₂NR⁴R⁵ or —NHSO₂R⁶;

-   -   R³ and R^(3′) are each independently hydrogen or methyl;    -   R⁴ and R⁵ are alkyl,    -   or R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form an optionally substituted piperazine ring; and    -   R⁶ is optionally substituted phenyl or optionally substituted        pyrolidinyl.

In some embodiments, the compounds are of formula (Ia), wherein

-   -   X¹ is —NR⁴R⁵, —NHC(O)R⁶, —NHSO₂NR⁴R⁵ or —NHSO₂R⁶;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   R⁴ and R⁵ are ethyl,    -   or R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form an optionally substituted piperazine ring; and    -   R⁶ is optionally substituted phenyl or optionally substituted        pyrolidinyl.

In some embodiments, the compounds are of formula (Ia), wherein

-   -   n is 1;    -   R³ i 3-methoxyphenyl; and    -   R⁴ and R⁵ are ethyl.

In some embodiments, the compounds are of formula (Ia), wherein

-   -   n is 0;    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form piperazine ring substituted with R⁷, wherein R⁷        is alkyl —SO₂R¹² or —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are alkyl,        -   R¹² is optionally substituted aryl; and    -   R⁶ is phenyl or pyrolidinyl, wherein the phenyl is substituted        with one ore more of halogen, haloalkyl, —O-haloalkyl,        —O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl, cyano,        -4-methoxyphenyl.

In some embodiments, the compounds are of formula (Ia), wherein R³ andR^(3′) are hydrogen.

In some embodiments, the compounds are of formula (Ia), wherein R³ ishydrogen and R^(3′) is methyl.

In some embodiments, the compounds are of formula (Ia), wherein whereinR³ and R^(3′) are methyl.

In some embodiments, the compounds are of formula (Ib).

wherein

-   -   X¹ is —NR⁴R⁵, —NHC(O)R⁶, —NHSO₂NR⁴R⁵ or —NHSO₂R⁶;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   when X¹ is —NR⁴R⁵, R⁴ and R⁵ together with the nitrogen atom to        which they are attached to form a piperazine ring, wherein the        piperazine ring substituted with R⁷, wherein R⁷ is —SO₂R¹² or        —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are alkyl; and        -   R¹² is phenyl substituted with halogen or —O-haloalkyl,    -   when X¹ is —NHC(O)R⁶, R⁶ is pyrrolidinyl,    -   when X¹ is —NHSO₂NR⁴R⁵, wherein R⁴ and R⁵ are alkyl, and    -   when X¹ is —NHSO₂R⁶, R⁶ is phenyl substituted with one or more        of —O-alkyl, halogen, haloalkyl, —O-haloalkyl,        —O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl or cyano;    -   provided that        -   a) when R⁶ is phenyl substituted with —O-alkyl, both R³ and            R^(3′) are methyl;        -   b) when R⁶ is phenyl substituted with one halogen, both R³            and R^(3′) are methyl;        -   c) when R⁶ is phenyl substituted with two halogens, both R³            and R^(3′) are hydrogen, or both R³ and R^(3′) are methyl;        -   d) when X¹ is —NHSO₂NR⁴R⁵, wherein R⁴ and R⁵ are alkyl, both            R³ and R^(3′) are methyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵, —NHC(O)R⁶, —NHSO₂NR⁴R⁵ or —NHSO₂R⁶;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   when X¹ is —NR⁴R⁵, R⁴ and R⁵ together with the nitrogen atom to        which they are attached to form a piperazine ring, wherein the        piperazine ring substituted with R⁷, wherein R⁷ is —SO₂R¹² or        —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are ethyl; and        -   R¹² is phenyl substituted with fluoro or —O—CF₃,    -   when X¹ is —NHC(O)R⁶, R⁶ is pyrrolidinyl,    -   when X¹ is —NHSO₂NR⁴R⁵, wherein R⁴ and R⁵ are ethyl, and    -   when X¹ is —NHSO₂R⁶, R⁶ is phenyl substituted with one or more        of —O—Me, fluoro, —CF₃, —O—CF₃,        —O-(5-(trifluoromethyl)pyridin-2yl), —O-phenyl or cyano;    -   provided that        -   a) when R⁶ is phenyl substituted with —OMe, both R³ and            R^(3′) are methyl;        -   b) when R⁶ is phenyl substituted with one fluoro group, both            R³ and R^(3′) are methyl;        -   c) when R⁶ is phenyl substituted with two fluoro groups,            both R³ and R^(3′) are hydrogen, or both R³ and R^(3′) are            methyl; and        -   d) when X¹ is —NHSO₂NR⁴R⁵, wherein R⁴ and R⁵ are ethyl, both            R³ and R^(3′) are methyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵ or —NHSO₂R⁶;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form a piperazine ring, wherein the piperazine ring        substituted with R⁷, wherein R⁷ is —SO₂R¹² or —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are alkyl; and        -   R¹² is phenyl substituted with halogen or —O-haloalkyl, and    -   R⁶ is phenyl substituted with one or more of —O-alkyl, halogen,        haloalkyl, —O-haloalkyl, —O-(5(trifluoromethyl)pyridin-2yl),        —O-phenyl or cyano;    -   provided that        -   a) when R⁶ is phenyl substituted with —O-alky, both R³ and            R^(3′) are methyl;        -   b) when R⁶ is phenyl substituted with one halogen, both R³            and R^(3′) are methyl; and        -   c) when R⁶ is phenyl substituted with two halogens, both R³            and R^(3′) are hydrogen, or both R³ and R^(3′) are methyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵ or —NHSO₂R⁶;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached to from a piperazine ring, wherein the piperazine ring        substituted with R⁷, wherein R⁷ is —SO₂R¹⁷ or —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are ethyl; and        -   R¹² is phenyl substituted with fluoro or —O—CF₃, and    -   R⁶ is phenyl substituted with one or more of —O—Me, fluoro,        —CF₃, —O—CF₃, —O-(5-(trifluoromethyl)pyridin-3-yl), —O-phenyl or        cyano;    -   provided that        -   a) when R⁶ is phenyl substituted with —OMe, both R³ and            R^(3′) are methyl;        -   b) when R⁶ is phenyl substituted with one fluoro group, both            R³ and R^(3′) are methyl;        -   c) when R⁶ is phenyl substituted with two fluoro groups,            both R³ and R^(3′) are hydrogen, or bother R³ and R^(3′) are            methyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form a piperazine ring, wherein the piperazine ring        substituted with R⁷, wherein R⁷ is —SO₂R¹² or —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are alkyl; and        -   R¹² is phenyl substituted with halogen or —O-haloalkyl,    -   provided that        -   a) when R⁶ is phenyl substituted with —O-alkyl, both R³ and            R^(3′) are methyl;        -   b) when R⁶ is phenyl substituted with one halogen, both R³            and R^(3′) are methyl; and        -   c) when R⁶ is phenyl substituted with two halogens, both R³            and R^(3′) are hydrogen, or both R³ and R^(3′) are methyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form a piperazine ring, wherein the piperazine ring        substituted with R⁷, wherein R⁷ is —SO₂R¹² or —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are ethyl; and        -   R¹² is phenyl substituted with fluoro or —O—CF₃.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NHSO₂R⁶;    -   R³ and R^(3′) are each independently hydrogen or methyl; and    -   R⁶ is phenyl substituted with one or more of —O-alkyl, halogen,        haloalkyl, —O-haloalkyl, —O-(5-(trifluoromethyl)pyridin-2-yl),        —O-phenyl or cyano;    -   provided that        -   a) when R⁶ is phenyl substituted with —O-alkyl, both R³ and            R^(3′) are methyl;        -   b) when R⁶ is phenyl substituted with one halogen, both R³            and R^(3′) are methyl; and        -   c) when R⁶ is phenyl substituted with two halogens, both R³            and R^(3′) are hydrogen, or both R³ and R^(3′) are methyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NHSO₂R⁶;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   R⁶ is phenyl substituted with one or more of —O—Me, fluoro,        —CF₃, —O—CF₃, —O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl or        cyano;    -   provided that        -   a) when R⁶ is phenyl substituted with —OMe, both R³ and            R^(3′) are methyl;        -   b) when R⁶ is phenyl substituted with one fluoro group, both            R³ and R^(3′) are methyl;        -   c) when R⁶ is phenyl substituted with two fluoro groups,            both R³ and R^(3′) are hydrogen, or both R³ and R^(3′) are            methyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NHC(O)R⁶ or —NHSO₂NR⁴R⁵;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   R⁶ is pyrrolidinyl; and    -   when X¹ is —NHSO₂NR⁴R⁵, wherein R⁴ and R⁵ are alkyl;    -   provided that        -   a) when R⁴ and R⁵ are alky, both R³ and R^(3′) are methyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NHC(O)R⁶ or —NHSO₂NR⁴R⁵;    -   R³ and R^(3′) are each independently hydrogen or methyl;    -   R⁶ is pyrrolidinyl; and    -   when X¹ is —NHSO₂NR⁴R⁵, wherein R⁴ and R⁵ are ethyl;    -   provided that        -   a) when R⁴ and R⁵ are ethyl, both R³ and R^(3′) are methyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵, —NHC(O)R⁶ or —NHSO₂R⁶;    -   R³ is hydrogen and R³ is hydrogen or methyl;    -   when X¹ is —NR⁴R⁵, R⁴ and R⁵ together with the nitrogen atom to        which they are attached to form a piperazine ring, wherein the        piperazine ring substituted with R⁷, wherein R⁷ is —SO₂R¹² or        —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are alkyl; and        -   R¹² is phenyl substituted with halogen or —O-haloalkyl,    -   when X¹ is —NHC(O)R⁶, R⁶ is pyrrolidinyl,    -   when X¹ is —NHSO₂R⁶, R⁶ is phenyl substituted with haloalkyl,        —O-haloalkyl, —O-(5-(trifluoromethyl)pyridin-2yl), —O-phenyl or        cyano.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵, —NHC(O)R⁶ or —NHSO₂R⁶;    -   R³ is hydrogen and R^(3′) is hydrogen or methyl;    -   when X¹ is —NR⁴R⁵, R⁴ and R⁵ together with the nitrogen atom to        which they are attached to form a piperazine ring, wherein the        piperazine ring substituted with R⁷, wherein R⁷ is —SO₂R¹² or        —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are ethyl; and        -   R¹² is phenyl substituted with fluoro or —O—CF₃,    -   when X¹ is —NHC(O)R⁶, R⁶ is pyrrolidinyl,    -   when X¹ is —NHSO₂R⁶, R⁶ is phenyl substituted with —CF₃, —O—CF₃,        —O-(5-trifluoromethyl)pyridin-2yl), —O-phenyl or cyano.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵ or —NHSO₂R⁶;    -   R³ is hydrogen and R^(3′) is hydrogen or methyl;    -   when X¹ is —NR⁴R⁵, R⁴ and R⁵ together with the nitrogen atom to        which they are attached to form a piperazine ring, wherein the        piperazine ring substituted with R⁷, wherein R⁷ is —SO₂R¹² or        —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are alkyl; and        -   R¹² is phenyl substituted with halogen or —O-haloalkyl,    -   when X¹ is —NHSO₂R⁶, R⁶ is phenyl substituted with haloalkyl,        —O-haloalkyl, —O-(5-(trifluoromethyl)pyridin-2yl), —O-phenyl or        cyano.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵ or —NHSO₂R⁶;    -   R³ is hydrogen and R^(3′) is hydrogen or methyl;    -   when X¹ is —NR⁴R⁵, R⁴ and R⁵ together with the nitrogen atom to        which they are attached to form a piperazine ring, wherein the        piperazine ring substituted with R⁷, wherein R⁷ is —SO₂R¹² or        —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are ethyl; and        -   R¹² is phenyl substituted with fluoro or —O—CF₃,    -   when X¹ is —NHSO₂R⁶, R⁶ is phenyl substituted with haloalkyl,        —O-haloalkyl, —O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl or        cyano.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵;    -   R³ is hydrogen and R^(3′) is hydrogen or methyl;    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached to form a piperazine ring, wherein the piperazine ring        substituted with R⁷, wherein R⁷ is —SO₂R¹² or —SO₂NR⁸R⁹, wherein        -   R⁸ and R⁹ are alkyl; and        -   R¹² is phenyl substituted with halogen or —O-haloalkyl.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NR⁴R⁵;    -   R³ is hydrogen and R^(3′) is hydrogen or methyl;    -   NR⁴R⁵, R⁴ and R⁵ together with the nitrogen atom to which they        are attached to form a piperazine ring, wherein the piperazine        ring substituted with R⁷, wherein R⁷ is —SO₂R¹² or —SO₂NR⁸R⁹,        wherein        -   R⁸ and R⁹ are ethyl; and        -   R¹² is phenyl substituted with fluoro or —O—CF₃.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NHSO₂R⁶;    -   R³ is hydrogen and R^(3′) is hydrogen or methyl;    -   R⁶ is phenyl substituted with haloalkyl, —O-haloalkyl,        —O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl or cyano.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NHSO₂R⁶;    -   R³ is hydrogen and R^(3′) is hydrogen or methyl;    -   R⁶ is phenyl substituted with haloalkyl, —O-haloalkyl,        —O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl or cyano.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NHSO₂R⁶;    -   R³ and R^(3′) are methyl;    -   R⁶ is phenyl substituted with one or more of —O-alkyl, halogen,        haloalkyl, —)— haloalkyl, —O—(5-(trifluoromethyl)pyridin-2-yl),        —O-phenyl or cyano.

In some embodiments, the compounds are of formula (Ib), wherein

-   -   X¹ is —NHSO₂R⁶;    -   R³ and R^(3′) are methyl;    -   R⁶ is phenyl substituted with one or more of —OMe, fluoro, —CF₃,        —O—CF₃, —O—(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl or        cyano.

In some embodiments, the compound isN-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)ethane-1-amineN-(2-(indolin-1-yl)ethyl)pyrrolidine-1-sulfonamide1,1-diethyl-3-(2-(indolin-1-yl)propyl)ureaN-(N,N-dimethylaminosulfonyl)-2-(indolin-1-yl)propane-1-amineN-(2-(indolin-1-yl)propyl)pyrrolidine-1-sulfonamideN-(2-(indolin-1-yl)ethyl)-4-methylpiperazine-1-carboxamideN-(2-(indolin-1-yl)ethyl)morpholine-4sulfonamideN-(2-(indolin-1-yl)ethyl)piperidine-1-sulfonamideN-(2-(indolin-1-yl)propyl)-4-methylpiperazine-1-carboxamideN-(2-(indolin-1-yl)propyl)pyrrolidine-1-carboxamideN-(2-(indolin-1-yl)ethyl)pyrrolidine-1-carboxamide1-(indolin-1-yl)-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethan-1-one1-(indolin-1-yl)-2-(4-(piperidin-1-ylsulfonyl)piperazin-1-yl)ethan-1-one4-(2-(indolin-1-yl)-2-oxoethyl)-N,N-dimethylpiperazine-1-sulfonamide1-(indolin-1yl)-3-(4-(piperidin-1-ylsulfonyl)piperazin-1-yl)propan-1-oneN-(2-(indolin-1-yl)propyl)-2-(pyridin-4-yl)thiazole-4-carboxamideN-(2-(indolin-1-yl)propyl)-4-methoxybenzenesulfonamideN-(2-(5-(3-methoxyphenyl)indolin-1-yl)-propyl)-N,N-diethyl-1-sulfonamideN-(2-(indolin-1-yl)propyl)-4-methylpiperazine-1-sulfonamideN-(2-(5-(3-methoxyphenyl)indolin-1-yl)propyl)-4-methylpiperazine-1-sulfonamideN-(N,N-diethylaminosulfonyl)-4-(indolin-1-yl)-phenyl-1-amineN-(2-(indolin-1-yl)propyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-2-(4-methoxyphenyl)thiazole-4-carboxamideN-(2-(indolin-1-yl)propyl)-2-phenylthiazole-4-carboxamideN-(2-(indolin-1-yl)propyl)-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide1-(2-(4-((4-trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl)indolineN,N-diethyl-4-(2-(indolin-1-yl)ethyl)piperazine-1-sulfonamide1-(2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl)indolineN,N-diethyl-4-(2-(indolin-1-yl)ethyl)piperazine-1-carboxamide1-(2-(4-(2-fluorobenzyl)piperazin-1-yl)ethyl)indolineN-(2-(indolin-1-yl)propyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-phenoxybenzenesulfonamide4-cyano-N-(2-(indolin-1-yl)propyl)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethyl)benzenesufonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-phenoxybenzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide3,4-difluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide4-cyano-N-(2-(indolin-1yl)ethyl)benzenesulfonamideN-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)-2-methylpropane-1-amineN-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-phenoxybenzenesulfonamide4-fluoro-N-(2-(indolin-1-yl)-2-methylpropyl)benzenesulfonamide3,4-difluoro-N-(2-(indolin-1-yl)-2-methylpropyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-(methoxy)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethoxy)benzenesulfonamideor a pharmaceutically acceptable salt thereof.

In some embodiments, the compound isN-(2-(indolin-1-yl)propyl)-4-methoxybenzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-(trifluoromethyl)benzenesulfonamide4-cyano-N-(2-(indolin-1-yl)propyl)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-phenoxybenzenesulfonamideN-(2-indolin-1-yl)propyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-phenoxybenzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-((5-(trifluoromethyl)pyridin-2yl)oxy)benzenesulfonamide3,4-difluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide4-cyano-N-(2-(indolin-1-yl)ethyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1yl)-2-methylpropyl)-4-phenoxybenzenesulfonamide4-fluoro-N-(2-(indolin-1-yl)-2-methylpropyl)benzenesulfonamide3,4-difluoro-N-(2-(indolin-1-yl)-2-methylpropyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-methoxybenzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)pyrrolidine-1-carboxamideN-(2-(indolin-1-yl)propyl)-4-methylpiperazine-1-carboxamideN-(2-(indolin-1-yl)propyl)-4-methylpiperazine-1-sulfonamideN-(N,N-diethylaminosulfonyl)-2-(5-(3-methoxyphenyl)indolin-1-yl)-propane-1-amineN-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)-2-methylpropane-1-amine1-(2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl)indoline1-(2-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl)indolineN,N-diethyl-4-(2-(indolin-1-yl)ethyl)piperazine-1-sulfonamideN,N-diethyl-4-(2-(indolin-1yl)ethyl)piperazine-1-carboxamide or apharmaceutically acceptable salt thereof.

In some embodiments, the compound isN-(2-(indolin-1-yl)propyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-phenoxybenzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide3,4-difluoro-N-(2-indolin-1-yl)ethyl)benzenesulfonamide4-cyano-N-(2-(indolin-1-yl)ethyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-phenoxybenzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-methoxybenzenesulfonamideN-(2-indolin-1-yl)-2-methylpropyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)-ethyl)pyrrolidine-1-carboxamideN-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)-2-methylpropane-1-amine1-(2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl)indoline1-(2-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl)indolineN,N-diethyl-4-(2-(indolin-1yl)ethyl)piperazine-1-sulfonamide or apharmaceutically acceptable salt thereof.

In some embodiments, the compound isN-(2-(indolin-1-yl)ethyl)-4-phenoxybenzenesulfonamideN-(2-indolin-1-yl)ethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide3,4-difluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide4-cyano-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide or apharmaceutically acceptable salt thereof.

In some embodiments, the compound is1-(2-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl)indolineN,N-diethyl-4-(2(indolin-1-yl)ethyl)piperazine-1-sulfonamide1-(2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl)indoline or apharmaceutically acceptable salt thereof.

It should be appreciated that various substituents on the compounds ofthe present invention can be present in the starting compounds, added toany one of the intermediate or added after formation of the finalproducts by known methods of substitution or conversion reactions. Ifthe substituents themselves are reactive, then the substituents canthemselves be protected according to the techniques known in the art. Avariety of protecting groups are known in the art, and can be employed.Examples of many of the possible groups can be found in “ProtectiveGroups in Organic Synthesis” by T. W. Green, John Wiley and Sons, 1981.For example, nitro groups can be added by nitration and the nitro groupcan be converted to other groups, such as amino by reduction, andhalogen by diazotization of the amino group and replacement of the diazogroup with halogen. Acyl groups can be added by Friedel-Craftsacylation. The acyl groups can then be transformed to the correspondingalkyl groups by various methods, including the Wolff-Kishner reductionand Clemmenson reduction. Amino groups can be alkylated to form mono-and di-alkylamino groups; and mercapto and hydroxy groups can bealkylated to form corresponding ethers. Primary alcohols can be oxidizedby oxidizing agents known in the art to form carboxylic acids oraldehydes, and secondary alcohols can be oxidized to form ketones. Thus,substitution or alteration reactions can be employed to provide avariety of substituents throughout the molecule of the startingmaterial, intermediates, or the final product, including isolatedproducts.

Still further, combinations of the various variable groups describedherein form other embodiments. In this manner, a variety of compoundsare embodied within the present invention.

In another aspect, the invention provides pharmaceutical compositions.In one embodiment, the pharmaceutical composition may include a compoundas described herein and a pharmaceutically acceptable carrier.

In another aspect, the compounds of the present invention are selectiveinhibitors of Nox4, and therefore can be used therapeutically for interalia treating a clinical condition associated with fibrotic disorder.

In some embodiments, the invention provides a method for treating aclinical condition associated with fibrotic disorder, the methodinvolving administering to a subject in need of such a treatment atherapeutically acceptable amount of a compound described herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition described herein, to treat the clinical condition associatedwith fibrotic disorder.

In some embodiments, the clinical condition associated with fibroticdisorder comprises fibrotic disease of the kidney, liver, skin, lung orheart.

In some embodiments, the clinical condition associated with fibroticdisorder comprises idiopathic pulmonary fibrosis.

The compounds of the present invention can be administered to a patientto achieve a desired physiological effect. The compound can beadministered in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous; intramuscular; subcutaneous; intraocular; intrasynovial;transepithelially including transdermal, opthalmic, sublingual andbuccal; topically including ophthalmic, dermal, ocular, rectal and nasalinhalation via insufflation and aerosol; intraperitoneal; and rectalsystemic. In some embodiments, administration is accomplished by oralinhalation, for example, through use of a mouth inhaler.

The active compound can be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it can beenclosed in hard or soft shell gelatin capsules, or it can be compressedinto tablets, or it can be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparation can contain at least0.1% of active compound. The percentage of the compositions andpreparation can, of course, be varied and can conveniently be betweenabout 1 to about 10% of the weight of the unit. The amount of activecompound in such therapeutically useful compositions is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared such that an oral dosageunit form contains from about 1 to about 1000 mg of active compound.

The tablets, troches, pills, capsules and the like can also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin can be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit from is a capsule, it can contain, in addition to materials of theabove type, a liquid carrier. Various other materials can be present ascoating or to otherwise modify the physical form of the dosage unit. Forinstance, tablets, pills, or capsules can be coated with shellac, sugaror both. A syrup or elixir can contain the active compound, sucrose as asweetening agent, ethyl and propylparabens a preservative, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any dosage unit form should be pharmaceutically pure andsubstantially non-toxic in the amounts employed. In addition, the activecompound can be incorporated into sustained-release preparations andformulation.

The active compound can also be administered parenterally. Solutions ofthe active compound as a free base or pharmacologically acceptable saltcan be prepared in water suitably mixed with a surfactant such ashydroxypropylcellulose. Dispersion can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It can be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorgansisms such as bacterial and fungi. Thecarrier can be a solvent of dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquidpolyethylene glycol, and the like), suitable mixtures thereof, andvegetable oils. The proper fluidity can be maintained, for example, bythe use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, e.g., sugars or sodium chloride. Prolonged absorption of theinjectable compositions of agents delaying absorption, e.g., aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousother ingredients enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thevarious sterilized active ingredient into a sterile vehicle whichcontains the basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques whichyield a powder of the active ingredient plus any additional desiredingredient from previously sterile-filtered solution thereof.

The therapeutic compounds of the present invention can be administeredto a mammal alone or in combination with pharmaceutically acceptablecarriers, as noted above, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmaceutical practice.

The therapeutic compounds of the present invention can be administeredin combination with one or more drugs for the treatment of idiopathicpulmonary fibrosis (IPF) and/or an antioxidant. For example, thecompounds of the present invention can be administered in combinationwith Pirfenidone, N-acetylcysteine, triple therapy (i.e.,N-acetylcysteine in combination with prednisone and azathioprine),Nintedanib or a combination thereof.

The physicians will determine the dosage of the present therapeuticagents which will be most suitable for prophylaxis or treatment and itwill vary with the form of administration and the particular compoundchosen, and also, it will vary with the particular patient undertreatment. The physician will generally wish to initiate treatment withsmall dosages by small increments until the optimum effect under thecircumstances is reached. The therapeutic dosage can generally be fromabout 0.1 to about 1000 mg/day, and preferably from about 10 to about100 mg/day, or from about 0.1 to about 50 mg/Kg of body weight per dayand preferably from about 0.1 to about 20 mg/Kg of body weight per dayand can be administered in several different dosage units. Higherdosages, on the order of about 2× to about 4×, may be required for oraladministration.

Additional objects, advantages, and novel features of this inventionwill become apparent to those skilled in the art upon examination of thefollowing examples thereof, which are not intended to be limiting. Inthe example, procedures that are constructively reduced to practice aredescribed in the present tense, and procedures that have been carriedout in the laboratory are set forth in the past tense.

EXAMPLES

The following abbreviations are used: HOBt (1-Hydroxybenzotriazole); DCM(Dichloromethane); EtOAc (Ethyl acetate); MeOH (Methanol); HBTU(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate); DIEA (N,N-diisopropylethylamine); DMF(N,N-dimethylformamide); Pd₂(dba)₃(Tris(dibenzylideneacetone)dipalladium(0)); Boc (t-Butyloxycarbonyl);(Box)₂O (Di-tert-butyl bicarbonate); AcOH (Acetic acid); EtOH (Ethanol);Et₃N (Triethylamine); TLC (Thin layer chromatography); and NMR (Nuclearmagnetic resonance).

General Procedure: All the chemicals were purchased from commercialvendors. All the solvents were obtained from Fischer Scientific Flashchromatography was performed with silica gel (230/400 mesh, FisherScientific). All anhydrous reactions were carried out under positivepressure of nitrogen. HPLC-MS analyses were performed on an Agilent 1100series instrument with Zorbax C18 reverse-phase column. The gradient was90 to 95 ACN in water over 20 minutes at 10 mL/min. The Chiral HPLCanalyses were performed on Agilent 1100 series instrument with ChiralcelOD-RH, 5 um, 4.6×150 mm column. HPLC purification of chiral compoundswere performed on Phenomenex Lux Amylose-2, Axia Packed, 5 um, 21.20×250mm. The solvent system used was 60% ACN in water isocratic run (nogradient) at 1 mL/min. HRMS results were obtained on an apex-Qeinstrument. All ¹H-NMR and ¹³C-NMR spectra were recorded on a BRUKERAVANCE-III 400 MHz NMR instrument, using deuterated solvents. Thespectra are reported in ppm and reference to deuterated DMSO (2.49 ppmfor ¹H, 39.5 ppm for ¹³C) or deuterated chloroform (7.26 ppm for ¹H, 77ppm for ¹³C). High-resolution mass spectra (HRMS) were acquired on aBruker 9.4 T Apex-Qh FTICR mass spectrometer. All the microwave assistedreactions were performed using a biotage initiator instrument. Allcompounds were analyzed for purity by HPLC using either MS or UVabsorbance detectors.

In a round bottomed flask equipped with a nitrogen inlet, a magneticstir bar and a reflux condenser, a solution of indoline (4.52 g, 35.68mmol, 4 mL) in 30 mL DMF was added. To the above solution, K₂CO₃ (14 g,101 mmol) was added and then the mixture was stirred for 30 min.Potassium iodide (0.58 g, 3.57 mmol, 0.1 eq) and 2-chloroethylaminehydrochloride (4.64 g, 39.25 mmol) were then added to the mixture. Themixture was then heated at 110° C. overnight. The reaction was thendiluted with 200 mL water, extracted with EtOAc (100 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, concentrated and thendried in vacuo yielding 8.35 g of the crude product. The crude was thendiluted with diethyl ether and then, 2 N HCl was added. The phases werethen separated, and the aqueous layer was then basified with 2.5 N NaOH.The aqueous was then extracted with EtOAc and the combined organiclayers were dried over anhydrous Na₂SO₂, concentrated and then dried invacuo yielding 6.32 g of the crude. The product was purified by a silicagel column chromatography using 1:1 EtOAc:hexanes to separate excessindoline and the desired product was eluted with 10% MeOH in CH₂Cl₂. Thecombined fractions were concentrated and then dried in vacuo to yield2.38 g (41%) of the brown oily compound as the desired product. ¹H NMR(400 MHz, CDCl₂) δ 7.10 (t, J=6.8 Hz, 1H), 7.07 (t, J=8 Hz, 1H), 6.71(t, J=8 Hz, 1H), 6.52 (d, J=8 Hz, 1H), 3.56 (q, J=8 Hz, 2H), 3.38 (t,J=8 Hz, 2H), 3.23 (t, J=8 Hz, 2H), 3.30 (t, J=8 Hz, 2H).

Compounds UANOX001(N-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)ethan-1-amine)

In a round bottomed flask equipped with a nitrogen inlet and a magneticstir bar, a solution of 0.21 g (1.22 mmol) of N,N-diethylsulfamoylchloride in 5 mL of CH₂Cl₂ was added. To the above solution 0.235 g (1mmol) of 2-(indolin-1-yl)ethan-1-amine dihydrochloride (i-2HCl) and 0.40mL (2.87 mmol) of triethylamine was added. The reaction was stirredvigorously at room temperature for 18 h and then, quenched using 20 mLwater. The aqueous layer was then extracted with CH₂Cl₂ (15 mL×3). Thecombined organic extracts were dried over anhydrous Na₂SO₄, concentratedand then dried in vacuo giving 0.40 g of the crude product. The crudewas then purified by column chromatography using 30% EtOAc in hexanes.The fractions were concentrated and then dried in vacuo yielding 170 mg(57%) of the desired product as light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.13 (d, J=8.0 Hz, 1H), 7.11 (t, J=8 Hz, 1H), 6.74 (t, J=8 Hz,1H), 6.57 (d, J=8 Hz, 1H), 4.63 (s, 2H), 3.38 (t, J=8 Hz, 2H), 3.32 (q,J=8 Hz, 4H), 3.28-3.23 (m, 4H), 3.02 (t, J=8 Hz, 2H), 1.23 (t, J=8 Hz,6H). HPLC-MS: Expected: 298 (MH⁺); Found: 298.

UANOX002 (1,1-diethyl-3-(2-(indolin-1-yl)ethyl)urea)

Compound UANOX002 was synthesized as per the procedure described forcompound UANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.09 (m, 2H), 6.74 (t,J=8 Hz, 1), 6.55 (d, J=8 Hz, 1H), 4.63 (bs, 1H), 3.38 (t, J=8 Hz, 2H),3.32 (quartet, J=8 Hz, 4H), 3.28-3.23 (m, 4H), 3.02 (t, J=8 Hz, 2H),1.23 (t, J=8 Hz, 6H). HPLC-MS: Expected: 262 (MH⁺); Found: 262.

UANOX003 (N-(N,N-dimethylaminosulfonyl)-2-(indolin-1-yl)ethan-1-amine)

UANOX003 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl3) δ 7.13 (d, J=8.0 Hz, 1H), 7.10 (t, J=8Hz, 1H), 6.74 (t, J=8 Hz, 1H), 6.56 (d, J=8 Hz, 1H), 4.69 (s, 1H), 3.39(t, J=8 Hz, 2H), 3.34-3.25 (m, 4H), 3.02 (t, J=8 Hz, 2H), 2.85 (s, 6H).HPLC-MS: Expected: 270 (MH⁺): Found: 270.

UANOX004 (N-(2(indolin-1-yl)ethyl)pyrrolidine-1-sulfonamide)

UANOX004 was synthesized as per the procedure described for compoundUANPX001 ¹H NMR (400 MHz, CDCl₃) δ 7.13 (d, J=8.0 Hz, 1H), 7.10 (t, J=8Hz, 1H), 6.74 (t, J=8 Hz, 1H), 6.56 (d, J=8 Hz, 1H), 4.70 (s, 1H), 3.39(t, J=8 Hz, 2H), 3.36-3.26 (m, 8H), 3.02 (t, J=8 Hz, 2H), 1.95 (s, 4H).HPLC-MS: Expected: 296 (MH⁺); Found: 296.

UANOX011 (N-(2-(indolin-1-yl)ethyl)-4-methylpiperazine-1-carboxamide)

UANOX001 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J=8 Hz, 1H), 7.08 (t, J=8Hz, 1H), 6.70 (t, J=8 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 4.65 (bs, 1H), 3.53(q, 4 Hz, 2H), 3.43 (t, J=8 Hz, 2H), 3.39-3.30 (m, 6H), 3.26 (t, J=8 Hz,2H), 2.85 (s, 3H), 1.9-1.88 (m, 2H, 1.86-1.82 (m, 2H). HPLC-MS: Expected310 (M+Na); Found: 310.

UANOX012 (N-(2-(indolin-1-yl)ethyl)morpholine-4-sulfonamide)

UANOX012 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.07 (m, 2H), 6.75 (t, J=8 Hz,1), 6.58 (d, J=8 Hz, 1H), 4.70 (bs, 1H), 3.78-3.75 (m, 6H), 3.39 (t, J=8Hz, 2H), 3.26-3.23 (m, 6H), 3.03 (t, J=8 Hz, 2H). HPLC-MS: Expected: 312(MH⁺); Found: 312.

UANOX021 (N-(2-(indolin-1-yl)ethyl)pyrrolidine-1-carboxamide)

UANOX021 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 7.12-7.06 (m, 2H), 6.70 (t, J=8 Hz, 1H), 6.57 (d,J=8 Hz, 1H), 4.61 (bs, 1H), 3.52 (quartet, J=8 Hz, 2H), 3.42 (t, J=8 Hz,2H), 3.32 (t, J=8 Hz, 4), 3.25 (t, J=8 Hz, 2H), 3.01 (t, J=8 Hz, 2H),1.90 (t, J=8 Hz, 4H). HPLC-MS: Expected: (MH⁺); Found: 260.

UANOX013 (N-(2-(indolin-1-yl)ethyl)-piperadine-1sulfonamide)

UANOX013 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, Chloroform-d) δ 7.23-6.99 (m, 2H), 6.76 (td,J=7.4, 0.9 Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 4.60 (bs, 1H), 3.40 (t,J=8.2 Hz, 2H), 3.36-3.26 (m, 4H), 3.25-3.20 (m, 4H), 3.02 (t, J=8.2 Hz,2H), 1.77-1.46 (m, 6H). HPLC-MS: Expected: 311 (M+2); Found: 311.

UANOX051 (4-fluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide)

UANOX051 was synthesized as per the procedure described for compoundUANOX001. ¹NMR (400 MHz, CDCl₃) ¹ H NMR (400 MHz, Chloroform-d) δ 7.92(dd, J=9.0, 5.1 Hz, 2H), 7.21 (t, J=9.2, 2H), 7.11 (d, J=7.2 Hz, 1H),7.07 (t, J=7.7 Hz, 1H), 6.73 (t, J=7.8 Hz, 1H), 6.39 (d, J=7.2 Hz, 1H),3.44-3.07 (m, 6H), 2.95 (t, J=8.2 Hz, 2H). HPLC-MS: Expected: 321 (MH⁺):Found: 321.

UANOX050 (4-methoxy-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide)

UANOX050 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J=9.2 Hz, 2H), 7.10(d, J=7.9 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 7.00 (d, J=9.1 Hz, 2H), 6.72(t, J=8 Hz, 1H), 6.38 (d, J=8.1 Hz, 1H), 3.90 (s, 3H), 3.24-3.12 (m,6H), 2.94 (t, J=8.3 Hz, 2H). HPLC-MS: Expected: 333 (MH⁺). Found: 333.

UANOX075 (4-trifluoromethyl-N-(2-(indolin-1-yl)benzenesulfonamide)

UANOX075 was synthesized as per the procedure described for compoundUANOX001.

¹H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.2Hz, 2H), 7.04 (d, J=7.2 Hz, 1H), 7.00 (t, J=7.7 Hz, 1H), 6.67 (t, J=7.4Hz, 1H), 6.29 (d, J=7.9 Hz, 1H), 5.08 (bs, 1H), 3.26-3.06 (m, 6H), 2.87(t, J=8.3 Hz, 2H), HPLC-MS: Expected: 371 (MH⁺): Found 371.

UANOX076(4-trifluoromethoxy-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide)

UANOX076 was synthesized as per the procedure described for compoundUANOX001.

¹H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J=9.7 Hz, 2H), 7.31 (d, J=8.7Hz, 2H), 7.05 (d, J=7.2 Hz, 1H), 7.01 (t, J=7.7 Hz, 1H), 6.68 (t, J=7.4Hz, 1H), 6.32 (d, J=7.2 Hz, 1H), 4.94 (bs, 1H), 3.25-3.04 (m, 6H), 2.89(t, J=7.7 Hz, 2H). HPLC-MS: Expected: 387 (MH⁺): Found: 387.

UANOX077 (N-(2-(indolin-1-yl)ethyl)benzo[d][1,3]dioxole-5-sulfonamide)

UANOX077 was synthesized as per the procedure described for compoundUANOX001.

¹H NMR (400 MHz, Chloroform-d) δ 7.41 (dd, J=8.2, 1.8 Hz, 1H), 7.23 (dd,J=7.2, 1.3 Hz, 1), 7.04 (d, J=7.2 Hz, 1H), 7.01 (t, J=7.7 Hz, 1H), 6.84(d, J=8.2 Hz, 1H), 6.66 (t, J=7.4 Hz, 1), 6.34 (d, J=7.9 Hz, 1H), 6.04(s, 2H), 4.83 (bs, 1H), 3.24-3.02 (m, 6H), 2.89 (t, J=8.2 Hz, 2).HPLC-MS: Expected: 347 (MH⁺); Found: 347

UANOX078(N-(2-(indolin-1-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide)

UANOX078 was synthesized as per the procedure described for compoundUANOX001.

¹H NMR (400 MHz, Chloroform-d) δ 7.37 (dd, J=2.2, 1.2 Hz, 1H), 7.32(ddd, J=8.5, 2.2, 1.3 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 7.01 (t, J=7.7Hz, 1H), 6.92 (dd, J=8.5, 0.9 Hz, 1H), 6.66 (t, J=7.4 Hz, 1H), 6.34 (d,J=7.9 Hz, 1H), 4.77 (bs, 1H), 4.35-4.12 (m, 4H), 3.22-3.00 (m, 6H), 2.89(t, J=8.2 Hz, 2H), HPLC-MS: Expected: 361 (MH⁺); Found: 361.

UANNOX079 (N-(2(indolin-1-yl)ethyl)-4-phenoxybenzenesulfonamide)

UANOX079 was synthesized as per the procedure described for compoundUANOX001.

¹H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J=8.8 Hz, 2H), 7.39 (t, J=8.0Hz, 2H), 7.20 (t, J=7.4 Hz, 1H), 7.08-6.85 (m, 6H), 6.67 (t, J=7.3 Hz,1), 6.34 (d, J=7.9 Hz, 1H), 4.86 (t, J=5.6 Hz, 1H), 3.21-3.06 (m, 6H),2.90 (t, J=8.2 Hz, 2H), HPLC-MS: Expected: 395 (MH⁺): Found: 395.

UANOX080(N-(2-(indolin-1-yl)ethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide)

UANOX080 was synthesized as per the procedure described for compoundUANOX808.

¹H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 7.95 (dd, J=8.6, 2.5 Hz,1H), 7.91 (d, J=8.9 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 7.09 (d, J=9.2 Hz,1H), 7.05 (d, J=7.2 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H), 6.67 (t, J=7.4 Hz,1H), 6.37 (d, J=7.8 Hz, 1H), 4.90 (t, J=5.7 Hz, 1H), 3.29-3.07 (m, 6H),2.91 (t, J=8.1 Hz, 2H). HPLC-MS: Expected: 464 (MH⁺); Found: 464.

UANOX082 (4-cyano-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide)

UANOX082 was synthesized as per the procedure described for compoundUANOX001.

¹H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J=7.7 Hz, 2H), 7.71 (d, J=7.4Hz, 2H), 7.04 (d, J=7.2 Hz, 1H), 7.00 (t, J=7.7 Hz, 1H), 6.68 (t, J=7.4Hz, 1H), 6.29 (d, J=7.9 Hz, 1H), 5.11 (bs, 1H), 3.27-3.03 (m, 6H), 2.87(t, J=8.2 Hz, 2H). ¹³C NMR (101 MHz, Chloroform-d) δ 151.68, 144.25,132.85, 129.77, 127.52, 127.32, 124.70, 118.87, 117.21, 116.26, 107.08,53.57, 49.57, 41.25, 28.49. HPLC-MS: Expected: 328 (MH⁺); Found: 328.

UANOX081 (3,4-difluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide)

UANNOX081 was synthesized as per the procedure described for compoundUANOX001.

¹H NMR (400 MHz, Chloroform-d) δ 7.67 (t, J=8.1 Hz, 1H), 7.61 (d, J=8.4Hz, 1H), 7.30-7.22 (m, 1H), 7.05-6.99 (m, 2H), 6.67 (t, J=7.3 Hz, 1H),6.34 (d, J=7.8 Hz, 1H), 4.94 (bs, 1H), 3.27-3.03 (m, 6H), 2.89 (t, J=8.1Hz, 2H). HPLC-MS: Expected: 339 (MH⁺); Found: 339.

Synthesis of UANOX017 (4-(2-(indolin-1-yl)ethyl)morpholine)

In a round bottomed flask equipped with a nitrogen inlet, a magneticstir bar and a reflux condenser, solution of indoline (0.2 mL, 0.213 g,1.78 mmol) in 2 mL DMF was added. To the above solution, K₂CO₃ (0.707 g,5.11 mmol) was added and then the mixture was stirred for 30 min.Potassium iodide (0.03 g, 0.19 mmol) and 4-(2-bromoethyl)morpholinehydrochloride (0.34 g, 1.78 mmol) were then added. The reaction mixturewas then heated at 110° C. for 6 hr. The mixture was then diluted withwater (20 mL) and then, extracted with EtOAc (15 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, concentrated and thendried in vacuo. The crude product was purified using columnchromatography, initially with 30% EtOAc in hexanes (to elute indoline)and then, with 10% MeOH in CH₂Cl₂ to obtain 0.246 g (59%) of the desiredproduct. ¹H NMR (400 MHz, CDCl₃) δ 7.04-7.00 (m, 2H), 6.60 (t, J=8 Hz,1H), 6.45 (d, J=8 Hz, 1H), 3.70 (t, J=4 Hz, 4H), 3.37 (t, J=8 Hz, 2H),3.20 (t, J=4 Hz, 2H), 2.93 (t, J=8 Hz, 2H), 2.58 (t, J=8 Hz, 2H), 2.51(m, 4H). HPLC-MS: Expected: 233 (MH⁺); Found: 233.

UANOX018 (1-(2-(piperidin-1-yl)ethyl)indoline)

UANOX018 was synthesized from indoline and 1-(2-bromoethyl)piperidineaccording to the procedure described for the synthesis of compoundUANOX017. ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.06 (m, 2H), 6.66 (t, J=8 Hz,1H), 6.52 (d, J=8 Hz, 1H), 3.42 (t, J=8 Hz, 2H), 3.28 (t, J=8 Hz, 2H),3.01-2.97 (m, 2H), 2.62 (t, J=8 Hz, 2H), 2.53 (t, J=8 Hz, 4H), 1.66(quintet, J=4 Hz, 4H), 1.52-1.47 (m, 2H). HPLC-MS: Expected: 231 (MH⁺);Found: 231.

Synthesis of 2-(indolin-1yl)propanamide (iia): In a round bottomed flaskequipped with a nitrogen inlet, a magnetic stir bara and a refluxcondenser, a solution of indoline (5.315 g, 44.6 mmol, 5 mL) in 42 mLDMF was added. To the above solution K₂CO₃ (18 g, 130 mmol) was addedand then the mixture was stirred for 30 min. Potassium iodide (0.8 g,4.91 mmol, 0.1 eq) and 2-bromopropiomamide (7.46 g, 49.06 mmol) werethen added to the mixture. The mixture was then heated at 110° C. or 2hr. The mixture was then diluted with water (200 mL), extracted withCH₂Cl₂ (70 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, concentrated and then dried in vacuo yielding 13.45 g of thecrude product. Crystals crashed out of the crude on standing for 48hours. The supernatant oil was removed and the crystals were washed withminimal amount of anhydrous diethyl ether. The product wasrecrystallized with anhydrous diethyl ether to give 1.65 g (19%) of pureproduct (found by NOESY to be one of the enantiomers). The supernatantwine color oily crude (11.5 g) was column chromatographed with 5% MeOHin CH₂Cl₂ to yield two fractions. ¹H NMR was used to confirm that thetwo fractions were the same compound. The combined organic layers of thetwo fractions containing the desired product were separatelyconcentrated and then dried in vacuo to obtain the desired product asbrown colored oil. This oily product turns solid on further drying. Thesolid was then washed with hexanes to remove excess DMF and the dried invacuo yielding 6.85 g (79%) of the desired product as brown solid.Overall yield is 98% ¹H NMR (400 MHz, CDCl₃) δ 7.14 (d, J=8.0 Hz, 1H),7.09 (t, J=8 Hz, 1H), 6.76 (t, J=8 Hz, 1H), 6.49 (d, J=8 Hz, 1H), 3.95(q, J=8 Hz, 1H), 3.49 (q, J=8 Hz, 1H), 3.42 (q, J=8 Hz, 1H), 3.02 (t,J=8 Hz, 2H), 1.43 (d, J=8 Hz, 3H), HPLC-MS: Expected: 191 (MH⁺); Found:191. 2-(indolin-1yl)-2-methylpropanamide (iib) was synthesized fromindoline and 2-bromo-2-methylpropanamide according to the proceduredescribed for the synthesis of compound iia. ¹H NMR (400 MHz,Chloroform-d) δ 7.27 (d, J=7.3 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 6.90 (t,J=7.4 Hz, 1H), 6.62 (d, J=7.9 Hz, 1H), 5.67 (bs, 1H), 3.56 (td, J=8.2,1.4 Hz, 2H), 3.11 (t, J=8.1 Hz, 2H), 2.13 (t, J=1.1 Hz, 3H), 1.57 (t,J=1.1 Hz, 3H), LCMS: Expected: 205 (MH⁺); Found: 205.

Synthesis of 2-(indolin-1-yl)propan-1-amine (iiia): A round bottomedflask equipped with a nitrogen inlet and a reflux condenser and2-(indolin-1-yl)propanamide (8.04 mmol, 1.53 g) was dissolved in 1MBH₃-THF (25 mL) was added. The reaction mixture was then heated toreflux for 18 h. The reaction mixture was allowed to cool to roomtemperature and then quenched slowly with MeOH. The solution wasconcentrated, dissolved in MeOH, and again concentrated. The resultingoil was diluted with diethyl ether and extracted twice with 1 N HCl. Theaqueous phase was treated with 2.5 N NaOH to adjust the pH>10 and then,extracted with EtOAc. the combined EtOAc extracts were dried overNa₂SO₄, and concentrated to provide 0.97 g of yellowish oil as crude.The crude product was purified by silica gel column chromatography using10-20% MeOH in CH₂Cl₂. The combined fractions were evaporated and thendried in vacuo yielding 0.78 g (55%) of the pure product as a mixture oftwo enantiomers. ¹H NMR (400 MHz, CDCl₃) δ 7.09-7.05 (m, 2H), 6.64 (t,J=8 Hz, 1H), 6.49 (d, J=8 Hz, 1H), 3.73-3.64 (m, 1H), 3.37 (quartet,J=8Hz, 1H), 3.29 (quartet, J=8 Hz, 1H), 2.99 (dd, J=8 Hz, 7 Hz, 2H),2.82 (ddd, J=36 Hz, 8 Hz, 12 Hz, 2H), 1.07 (d, J=8 Hz, 3H).

2-(indolin-1-yl)-2-methylpropan-1-amine (iiib) was synthesized accordingto the procedure described for the synthesis of compound iiia. ¹H NMR(400 MHz, Chloroform-d) δ 7.31 (d, J=7.6 Hz, 1H), 7.24 (t, J=8.1 Hz,1H), 7.00 (d, J=7.9 Hz, 1H), 6.88 (t, J=7.3 Hz, 1H), 3.68 (t, J=8.6 Hz,2H), 3.20 (s, 2H), 3.14 (t, J=8.6 Hz, 2H), 1.85-1.64 (bs, 1H), 1.63 (d,J=30.5 Hz, 3H), 1.55 (s, 3H). LCMS: Expected: 191 (MH⁺); Found: 191.

UANOX006 (1,1-diethyl-3-(2-(indolin-1-yl)propyl)urea)

UANOX006 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.09-7.05 (m, 2H), 6.65 (t, J=8 Hz,1H), 6.52 (d, J=8 Hz, 1H), 4.73 (bs, 1H), 3.93-3.81 (m, 1H), 3.60-3.54(ddd, J=20, 12, 8 Hz, 1H), 3.34-3.29 (m, 2H), 3.33-3.31 (m, 5H),3.24-3.91 (m, 2H), 1.14 (d, J=8 Hz, 3H), 1.06 (t, J=8 Hz, 6H). Minorconformer was also observed in proton NMR: ¹H NMR (400 MHz, CDCl₃) δ7.62 (dq, J=8, 0.8 Hz), 7.42 (dq, J=8, 0.8 Hz), 7.21 (d, J=3.6 Hz), 7.19(dt, J=8.12 Hz), 7.13 (dd, J=20, 1.2 Hz), 6.58 (d, J=3.6 Hz), 1.60 (d,J=8 Hz), 0.87 (t, J=8 Hz). HPLC-MS: Expected: 276 (MH⁺); Found: 276.

UANOX007 (N-(N,N-dimethylaminosulfonyl)-2-(indolin-1-yl)propane-1-amine)

UANOX007 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.127.07 (m, 2H), 6.71 (t, J=8 Hz,1H), 6.52 (d, J=8 Hz, 1H), 4.80 (bs, 1 H), 3.93-3.84 (m, 1H), 3.40-3.26(m, 2H), 3.19 (t, J=8 Hz, 2H), 3.02-2.98 (m, 2H), 2.82 (s, 6H), 1.11 (d,J=6.8 Hz, 3H). HPLC-MS: Expected: 284 (MH⁺); Found: 284.

UANOX008 (N-(2-(indolin-1-yl)propyl)-pyrrolidine-1-sulfonamide)

UANOX008 was synthesized as per the procedure described for compoundUANOX001. 7.14-7.07 (m, 2H), 6.70 (t, J=8 Hz, 1H), 6.51 (d, J=8 Hz, 1H),4.79-4.74 (m, 1H), 3.87 (sextet, J=7 Hz, 1H), 3.39-3.25 (m, 6H),3.22-3.18 (m, 2H), 3.14 (t, J=8 Hz, 1H), 3.02-2.97 (m, 2H), 1.97-1.91(m, 4H), 1.11 (d, J=6.4 Hz, 3H). HPLC-MS: Expected: 310 (MH⁺); Found:310.

UANOX019 (N-(2-(indolin-1-yl)propyl)-4-methylpiperazine-1-carboxamide)

UANOX019 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.09-7.04 (m, 2H), 6.65 (t, J=8 Hz,1H), 6.51 (d, J=8 Hz, 1H), 3.89-3.81 (m, 1H), 3.58-3.52 (ddd, J=20, 12,8 Hz, 1H), 3.36-3.19 (m, 7H), 3.00-2.96 (m, 2H), 2.34 (t, J=5 Hz, 4H),2.29 (s, 3H), 1.12 (d, J=8 Hz, 3H). HPLC-MS: Expected: 304 (M+2); Found:304.

UANOX010 (N-(2-(indolin-1-yl)propyl)morpholine-4-sulfonamide)

UANOX010 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.12 (d, J=8 Hz, 1H), 7.09 (t, J=8Hz, 1H), 6.71 (t, J=8 Hz, 1H), 6.51 (d, J=8 Hz, 1H), 4.78 (t, J=8 Hz,1H), 3.913.83 (m, 1H), 3.77 (t, J=8 Hz, 4H), 3.38-3.25 (m, 2H),3.23-3.20 (m, 6H), 3.02-2.98 (m, 2H), 1.12 (d, J=8 Hz, 3H). HPLC-MS:Expected: 326 (MH⁺); Found: 326 and Expected: 348 (M⁺+Na); Found: 348.

UANOX020 (N-(2-(indolin-1-yl)propyl)pyrrolidine-1-carboxamide)

UANOX020 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.05 (m, 2H), 6.66 (t, J=8 Hz,1H), 6.53 (d, J=8 Hz, 1H), 4.56 (bs, 1H), 3,92-3.84 (m, 1H), 3.62-3.56(ddd, J=20, 12, 8 Hz, 1H), 3.42-3.31 (m, 2H), 3.27-3.19 (m, 5H),3.02-2.97 (m, 2H), 1.89-1.83 (m, 4H), 1.14 (d, J=8 Hz, 3H). HPLC-MS.Expected: 274 (MH⁺); Found: 274.

UANOX009 (N-(2-(indolin-1-yl)propyl)piperidine-1-sulfonamide)

UANOX009 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.07 (m, 2H), 6.71 (t, J=8 Hz,1H), 6.52 (d, J=8 Hz, 1H), 4.76 (t, J=8 Hz, 1H), 3.91-3.82 (m, 1H),3.40-3.26 (m, 2H), 3.21-3.16 (m, 6H), 3.02-2.98 (m, 2), 1.69-1.62 (m,4H), 1.61-1.53 (m, 2H), 1.11 (d, J=6.8 Hz, 3H). HPLC-MS: Expected: 324(MH⁺); Found: 324.

UANOX033(N-(2-(indolin-1-yl)propyl)-2-(pyridin-4-yl)thiazole-4-carboxamide)

In a round bottomed flask equipped with a magnetic stir bar and anitrogen inlet, a mixture of 2-(indolin-1yl)propan-1-amine (iii) (0.15g, 0.60 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.149 g, 0.72mmol) and HOBT-hydrate (0.11 g, 0.72 mmol) in 6 mL DMF were added. Tothe above solution, HBTU (0.27 g, 0.72 mmol) and diisopropylamine (0.28mL, 1.60 mmol) were also added. The mixture was stirred at roomtemperature for 16 h. To the reaction mixture, aqueous saturated K₂CO₃solution was added and then extracted with CH₂Cl₂. The combined organiclayers were then washed with water, brine, dried over Na₂SO₄, andconcentrated. The crude was purified by column chromatography with 0-2%MeOH in CH₂Cl₂. The compound was further purified by HPLC to give 20 mg(9%) of the pure and desired compound. ¹H NMR (400 MHz, CDCl₃) δ 8.71(d, J=6 Hz, 2H), 8.22 (s, 1H), 7.71 (d, J=6 Hz, 2H), 7.68 (bs, NH), 7.11(d, J=7 Hz, 1H), 7.07 (t, J=7 Hz, 2H), 6.66 (t, J=7 Hz, 1), 6.56 (d, J=7Hz, 1H), 4.06-3.97 (m, 1H), 3.79 (ddd, J=13.8, 7.0, 5.3 Hz, 1H),3.62-3.31 (m, 3H), 3.04 (t, J=9 Hz, 2H), 1.24 (d, J=9 Hz, 3H). HPLC-MS:Expected: 365 (MH⁺); Found: 365.

UANOX034 (N-(2-(indolin-1-yl)propyl)-4-methoxybenzenesulfonamide)

UANOX034 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J=8 Hz, 2H), 7.09-7.04 (m,2H), 7.01 (d, J=8 Hz, 2H), 6.69 (t, J=8 Hz, 1H), 6.31 (d, J=8 Hz, 1H),4.94-4.91 (m, 1H), 3.92 (s, 3H), 3.73-3.64 (m, 1H), 3.20-3.11 (m, 2H),3.06-2.96 (m, 2H), 2.94-2.84 (m, 2H), 1.01 (d, J=8 Hz, 3H). HPLC-MS:Expected: 347 (MH⁺); Found: 347.

UANOX035 (4-fluoro-N-(2-(indolin-1-yl)propyl)benzenesulfonamide)

UANOX035 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.93-7.89 (m, 2H), 7.22 (t, J=8 Hz,2H), 7.09 (d, J=8 Hz, 1H), 7.05 (t, J=8 Hz, 1H), 6.71 (t, J=8 Hz, 1H),6.32 (d, J=8 Hz, 1H), 4.98 (d, J=8 Hz, 1H), 3.75-3.66 (m, 1H), 3.23-3.13(m, 2H), 3.08-2.86 (m, 4H), 1.03 (d, J=8 Hz, 3H). HPLC-MS: Expected: 335(MH⁺); Found: 335. The racemic mixture was separated by preparatorychiral HPLC.

Enantiomer A: ¹H NMR (400 MHz, CDCl₃) δ 7.92-7.89 (m, 2H), 7.21 (t, J=8Hz, 2H), 7.09 (d, J=8 Hz, 1H), 7.07 (t, J=8 Hz, 1H), 6.69 (t, J=8 Hz,1H), 6.32 (d, J=8 Hz, 1H), 5.07 (bs, 1H), 3.74-3.66 (m, 1H), 3.21-3.13(m, 2H), 3.09-2.85 (m, 4H), 1.04 (d, J=8 Hz, 3H). HPLC-MS: Expected: 335(MH⁺); Found: 335.

Enantiomer B: ¹NMR (400 MHz, CDCl₃) δ 7.92-7.89 (m, 2H), 7.21 (t, J=8Hz, 2H), 7.09 (d, J=8 Hz, 1H), 7.07 (t, J=8 Hz, 1H), 6.69 (t, J=8 Hz,1H), 6.32 (d, J=8 Hz, 1H), 5.07 (bs, 1H), 3.74-3.66 (m, 1H), 3.21-3.13(m, 2H), 3.09-2.85 (m, 4H), 1.04 (d, J=8 Hz, 3H). HPLC-MS: Expected: 335(MH⁺); Found: 335.

UANOX037 (4-hydroxy-N-(2-(indolin-1-yl)propyl)piperazine-1-sulfonamide)

UANOX037 was synthesized as per the procedure described for compoundUANOX001. ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.07 (m, 2H), 6.70 (t, J=8 Hz,1H), 6.51 (d, J=8 Hz, 1H), 5.14 (bs, 1H), 3.92-3.84 (m, 1H), 3.74 (bs,4H), 3.40-3.34 (m, 2H), 3.19 (t, J=8 Hz, 2H), 2.99 (t, J=8 Hz, 2H), 2.75(bs, 4H), 2.49 (bs, 3H), 1.11 (d, J=6.8 Hz, 3H). HPLC-MS: Expected:339(MH⁺); Found: 339.

UANOX049(N-(2-(indolin-1-yl)propyl-4-(trifluoromethoxy)benzenesulfonamide)

UANOX049 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 7.93 (d, J=12 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 7.08(d, J=8 Hz, 1H), 7.04 (t, J=8 Hz, 1H), 6.70 (t, J=8 Hz, 1H), 6.30 (d,J=8 Hz, 1), 5.17 (dd, J=8.4, 2.3 Hz, 1H), 3.74-3.66 (m, 1H), 3.32-3.13(m, 2H), 3.09-3.00 (m, 2H), 2.97-2.84 (m, 2H), 1.05 (d, J=6.8 Hz, 3H).HPLC-MS: Expected: 401 (MH⁺); Found: 401.

UANOX048(N-(2-(indolin-1-yl)propyl)-4-(trifluoromethyl)benzenesulfonamide)

UANOX048 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 8.01 (d, J=7.6 Hz, 2H), 7.78 (d, J=8.2 Hz,2H), 7.08 (d, J=8.3 Hz, 1H), 7.04 (t, J=7.1 Hz, 1H), 6.70 (t, J=7.8 Hz,1H), 6.28 (d, J=7.9 Hz, 1H), 5.32-5.26 (m, 1H), 3.77-3.64 (m, 1H),3.29-2.77 (m, 6H), 1.05 (d, J=6.7 Hz, 3H). HPLC-MS: Expected: 385 (MH⁺);Found: 385.

UANOX055 (N-(2-(indolin-1-yl)propyl)-2phenylthiazole-4-carboxamide)

UANOX055 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.90-7.87 (m, 2H), 7.71 (s, NH),7.4-7.44 (m, 3H), 7.12-7.06 (m, 2H), 6.67 (t, J=8 Hz, 1H), 6.57 (d, J=8Hz, 1H), 4.01 (dp, J=9.4, 6.6 Hz, 1H), 3.78 (ddd, J=13.7, 7.0, 5.6 Hz,1H), 3.59-3.39 (m, 3H), 3.04 (t, J=8 Hz, 2H), 3.03 (d, J=8 Hz, 3H).HPLC-MS: Expected: 364 (MH⁺); Found: 364.

UANOX073 (4-fluoro-N-(2-(indolin-1-yl)propyl)benzenesulfonamide

UANOX073 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 7.98 (d, J=8.7 Hz, 1), 7.80 (d, J=8.7 Hz,1H), 7.11-7.00 (m, 2H), 6.72 (t, J=7.8 Hz, 1H), 6.30 (d, J=7.9 Hz, 1H),5.15 (d, J=6.9 Hz, 1H), 3.80-3.52 (m, 1H), 3.31-3.13 (m, 2H), 3.13-3.00(m, 2H), 2.98-2.83 (m, 2H), 1.06 (d, J=6.7 Hz, 3H). HPLC-MS: Expected:342 (MH⁺); Found: 342.

UANOX056(N-(2-(indolin-1-yl)propyl-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide)

UANOX056 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 8.53 (s, 1H), 8.34 (d, J=8 Hz, 2H), 8.06 (d,J=12, 2H+1NH), 7.48 (d, J=8 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.03 (t, J=8Hz, 1H), 6.92 (d, J=8 Hz, 1H), 4.40-4.34 (m, 1H), 4.18-4.12 (m, 1H),3.93-3.75 (m, 3H), 3.39 (d, J=8 Hz, 2H), 1.59 (d, J=8 Hz, 3H). HPLC-MS:Expected: 432 (MH⁺); Found: 432.

UANOX054(N-(2-(indolin-1-yl)propyl)-2-(4-(methoxy)phenyl)thiazole-4-carboxamide

UANOX05 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.71 (s, NH),7.11 (d, J=8 Hz, 1H), 7.09 (t, J=8 Hz, 1H), 6.96 (d, J=8 Hz, 2H), 6.66(t, J=8 Hz, 1H), 6.57 (d, J=8 Hz, 1H), 4.03-3.97 (m, 1H), 3.89 (s, 3H),3.81-3.74 (m, 1H), 3.58-3.39 (m, 3H), 3.04 (t, J=8 Hz, 2H), 1.23 (d, J=8Hz, 3H). HPLC-MS: Expected: 394 (MH⁺); Found: 394.

UANOX069(N-(2-(indolin-1-yl)propyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide)

UANOX069 was synthesized as per the procedure for UANOX001. ¹H NMR (400MHz, Chloroform-d) δ 7.42 (d, J=2.2 Hz, 1H), 7.37 (dd, J=8.4, 2.2 Hz,1H), 7.13-7.02 (m, 2H), 6.98 (d, J=8.7 Hz, 1H), 6.69 (td, J=7.4, 0.9 Hz,1H), 6.34 (d, J=7.9 Hz, 2H), 4.89 (d, J=8.8 Hz, 1H, NH), 4.41-4.20 (m,4H), 3.76-3.66 (m, 1H), 3.21-3.10 (m, 2H), 3.06 (td, J=8.4, 4.4 Hz, 1H),2.99 (ddd, J=12.7, 10.5, 2.4 Hz, 1H), 2.95-2.89 (m, 2H), 1.04 (d, J=6.7Hz, 3H). HPLC-MS: Expected: 375 (MH⁺); Found: 375.

UANOX071 (N-(2-(indolin-1-yl)propyl)-4-phenoxyvenzenesulfonamide)

UANOX071 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 7.84 (d, J=8.9 Hz, 2H), 7.45 (dd, J=8.5,7.5 Hz, 2H), 7.28-7.21 (m, 1H), 7.13-7.01 (m, 6H), 6.70 (t, J=7.4 Hz,1H), 6.33 (d, J=7.9 Hz, 1H), 4.97 (d, J=9.6 Hz, 1H, NH), 3.80-3.51 (m,1H), 3.24-3.12 (m, 2H), 3.07 (dt, J=8.6, 4.0 Hz, 1H), 3.01 (dt, J=12.6,10.4, 1H), 2.98-2.83 (m, 2H), 1.05 (d, J=6.7 Hz, 3H). HPLC-MS: Expected:409 (MH⁺): Found: 409.

UANOX070(N-(2-(indolin-1-yl)propyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide)

UANOX070 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 8.47 (dt, J=2.6, 0.9 Hz, 1H), 8.01 (ddd,J=8.6, 2.5, 0.6 Hz, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.33 (d, J=9.0 Hz, 2H),7.15 (dp, J=8.6, 0.6 Hz, 1H), 7.09 (d, J=7.1 Hz, 1H), 7.04 (t, J=7.7 Hz,1H), 6.71 (dd, J=7.4, 0.8 Hz, 1H), 6.37 (d, J=7.9 Hz, 1H), 5.02 (d,J=9.7 Hz, 1H, NH), 3.72 (dt, J=11.1, 6.8 Hz, 1H), 3.33-3.14 (m, 2H),3.14-3.00 (m, 2H), 2.99-2.87 (m, 2H), 1.06 (d, J=6.7 Hz, 3H). HPLC-MS:Expected: 478 (MH⁺); Found: 478.

UANOX072 (3,4-difluoro-N-(2-(indolin-1-yl)propyl)benzenesulfonamide)

UANOX072 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 7.73 (ddd, J=9.3, 7.2, 2.2 Hz, 1H),7.70-7.63 (m, 1H), 7.33 (ddd, J=9.6, 8.6, 7.3 Hz, 1H), 7.12-7.02 (m,2H), 6.71 (t, J=7.4 Hz, 1H), 6.35 (d, J=7.9 Hz, 1H), 5.07 (d, J=9.8 Hz,1H, NH), 3.73 (dt, J=11.0, 6.8 Hz, 1H), 3.28-3.14 (m, 2H), 3.10 (td,J=8.7, 4.1 Hz, 1H), 3.02 (tdd, J=12.6, 10.4, 2.4 Hz, 1H), 2.96-2.89(m,2H), 1.06 (d, J=6.7 Hz, 3H). HPLC-MS: Expected: 353 (MH⁺); Found: 353.

UANOX083(N-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)-2-methylpropane-1-amine)

UANOX083 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 6.69 (d, J=7.5 Hz, 1H), 6.61 (t, J=8.1 Hz,1H), 6.45-6.02 (m, 2H), 4.25 (t, J=6.4 Hz, 1H), 3.00 (t, J=8.6 Hz, 2H),2.93-2.74 (m, 6H), 2.49 (t, J=8.3 Hz, 2H), 0.95 (s, 6H), 0.78 (t, J=7.1Hz, 6H). HPLC-MS: Expected: 326 (MH⁺); Found: 326.

UANOX084(N-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethyl)benzenesulfonamide)

UANOX084 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 7.81 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.4 Hz,2H), 6.95 (d, J=7.1 Hz, 1H), 6.63 (t, J=7.7 Hz, 1H), 6.56 (d, J=7.7 Hz,1H), 6.06 (d, J=7.9 Hz, 1H), 5.02 (t, J=5.4 Hz, 1H), 3.24 (t, J=8.3 Hz,2H), 3.12 (d, J=5.4 Hz, 2H), 2.76 (t, J=8.3 Hz, 2H), 1.19 (s, 6H).HPLC-MS: Expected: 399 (MH⁺); Found: 399.

UANOX085(N-(2-(indolin-1-yl)-2-methylpropyl)-4-phenoxybenzenesulfonamide)

UANOX085 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 7.98 (d, J=8.9 Hz, 2H), 7.67 (t, J=7.9 Hz,2H), 7.52-7.43 (m, 1H), 7.33 (d, J=7.8 Hz, 2H), 7.29 (d, J=7.0 Hz, 1H),7.24 (d, J=8.9 Hz, 2H), 7.06 (t, J=7.7 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H),6.51 (d, J=8.0 Hz, 1H), 5.20 (t, J=5.6 Hz, 1H), 3.59 (t, J=8.3 Hz, 2H),3.44 (d, J=5.6 Hz, 2H), 3.11 (t, J=8.3 Hz, 2H), 1.53 (s, 6H). HPLC-MS:Expected: 423 (MH⁺); Found: 423.

UANOX086(4-fluoro-N-(2-(indolin-1-yl)-2-methylpropyl)benzenesulfonamide)

UANOX086 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 7.85-7.81 (m, 2H), 7.18 (td, J=8.6, 2.6Hz, 2H), 7.09 (d, J=7.0 Hz, 1H), 6.81 (t, J=7.9 Hz, 1H), 6.69 (td,J=7.4, 2.2 Hz, 1H), 6.24 (dd, J=8.1, 2.2 Hz, 1H), 5.02 (s, 1H), 3.37(td, J=8.3, 2.5 Hz, 2H), 3.22 (dd, J=5.6, 2.6 Hz, 2H), 2.90 (t, J=8.0Hz, 2H), 1.31 (s, 6H). HPLC-MS: Expected: 349 (MH⁺); Found: 349.

UANOX087(3,4-difluoro-N-(2-(indolin-1yl)-2-ethylpropyl)benzenesulfonamide)

UANOX087 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 7.69 (t, J=9.2 Hz, 1H), 7.67-7.58 (m, 1H),7.31 (q, J=8.0 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H),6.73 (t, J=7.3 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H), 5.13 (s, 1H), 3.41 (t,J=8.3 Hz, 2H), 3.27 (d, J=5.4 Hz, 2H), 2.93 (t, J=8.2 Hz, 2H), 1.35 (s,6H). LCMS: Expected (M+H): 367 (M+H)⁺ and 389 (M+Na)⁺; Found: 367 and389.

UANOX088(N-(2-(indolin-1-yl)-2-methylpropyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide)

UANOX088 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 7.94 (dd, J=8.5, 2.6 Hz,1H), 7.81 (d, J=8.9 Hz, 2H), 7.26-7.20 (m, 2H), 7.08 (d, J=8.1 Hz, 1H),7.02 (d, J=7.9 H, 1H), 6.81 (t, J=7.7 Hz, 1H), 6.61 (t, J=7.3 Hz, 1H),6.23 (d, J=8.0 Hz, 1H), 4.94 (t, J=5.8 Hz, 1H), 3.32 (t, J=8.4 Hz, 2H),3.20 (d, J=5.5 Hz, 2H), 2.84 (t, J=8.4 Hz, 2H), 1.26 (s, 6H). LCMS:Expected: 492 (MH⁺); Found: 492.

UANOX089(N-(2-(indolin-1-yl)-2-methylpropyl)-4-methoxybenzenesulfonamide)

UANOX089 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 7.77 (d, J=10.7 Hz, 2H), 7.10 (d, J=7.3Hz, 1H), 6.99 (d, J=7.2 Hz, 2H), 6.82 (t, J=8.0 Hz, 1H), 6.69 (t, J=7.8Hz, 1H), 6.26 (d, J=7.9 Hz, 1H), 4.93 (t, J=5.5 Hz, 1H), 3.94 (s, 3H),3.39 (t, J=8.7 Hz, 2H), 3.21 (d, J=7.1 Hz, 2H), 2.91 (t, J=8.3 Hz, 2H),1.33 (s, 6H). LCMS: Expected: 361 (MH⁺); Found: 361.

UANOX090(N-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethoxy)benzenesulfonamide)

UANOX090 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, Chloroform-d) δ 7.84 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.3 Hz,2H), 7.06 (d, J=7.1 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.67 (d, J=7.3 Hz,1H), 6.20 (d, J=8.0 Hz, 1H), 5.09 (s, 1H), 3.35 (t, J=8.3 Hz, 2H), 3.22(d, J=5.4 Hz, 2H), 2.87 (t, J=8.3 Hz, 2H), 1.29 (s, 6H). LCMS: Expected:415 (M+H) and 437 (M+Na); Found: 415 and 437.

Synthesis of tert-butyl 5-bromoindoline-1-carboxylate (iv): To a roundbottomed flask equipped with a nitrogen inlet and a magnetic stir bar, asolution of 5-bromoindoline (5 g, 25.24 mmol) in 200 mL MeOH was added.To the above solution, K₂CO₃ (4.2 g, 30.89 mmol) was added and then thereaction was stirred for 30 min followed by addition of boc anhydride(7.0 g, 32.07 mmol). The mixture was then stirred at room temperaturefor 72 hr, then diluted with water (300 mL). The aqueous mixture wasextracted with CH₂Cl₂ (100 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄. concentrated to obtain 7.25 g of crude. The crudewas purified by column chromatography. The desired compound was elutedwith 10-20% EtOAc in hexanes yielding 5.65 g (75%) of the desiredproduct. ¹H NMR (400 MHz, CDCl₃) δ 7.28 (bs, 3H), 4.00 (t, J=8 Hz, 2H),3.10 (t, J=8 Hz, 2H), 1.58 (s, 9H).

Synthesis of tert-butyl 5-(3-methoxyphenyl)indoline-1-carboxylate (v):In a round bottomed flask equipped with a magentic stir bar and anitrogen inlet, a solution of tert-butyl 5-bromoindoline-1-carboxylate(1.2 g, 4.04 mmol) and (3-methoxyphenyl)boronoic acid (0.73 g, 4.80mmol), Na₂CO₃ (0.852 g, 8.04 mmol) and Pd(PPh₃)₃ (0.464 g, 0.40 mmol) in24 mL of DMF/H₂O (1:1) were added. The reaction mixture was heated at90° C. for 18 hr. The reaction mixture was then cooled to roomtemperature and 80 mL of water was added. The aqueous was then extractedwith CH₂Cl₂ (50 mL×4), dried over Na₂SO₄, concentrated to yield 2.53 gblack oil. The crude product was then purified by column chromatographywith 10-20% EtOAc in hexanes to give 0.846 g (64%) of the desiredcompound as a white solid ¹H NMR (400 MHz, Chloroform-d) δ 7.44-7.38 (m,3H), 7.35 (t, J=7.9 Hz, 1H), 7.17 (ddd, J=7.1, 1.7, 1.0 Hz, 1H), 7.11(dd, J=2.4, 1.7 Hz, 1H), 6.88 (ddd, J=8.2, 2.6, 0.9 Hz, 1H), 4.07 (t,J=8 Hz, 2H), 3.89 (s, 3H), 3.17 (t, J=8 Hz, 2H), 1.61 (s, 9H).

Synthesis of 5-(3-methoxyphenyl)indoline (vi): In a round bottomed flaskequipped with a nitrogen inlet and a magnetic stir bar, the solution oftert-butyl 5-(4-methoxyphenyl)indoline-1-carboxylate (0.846 g, 2.6 mmol)in 40 mL CH₂Cl₂ was added. To the above solution, 11 mL CF₃COOH wasadded and the mixture was stirred at room temperature for overnight. Thereaction was monitored by TLC. After completion of the reaction, solventwas removed. The residue was dissolved in water and then, saturatedaqueous Na₂Co₃ solution was added to adjust pH=11. The aqueous layer wasthen extracted with CH₂Cl₂ (30 mL×3). The combined organic layers wereconcentrated and then dried in vacuo to give 0.60 mg (100%) of thedesired product. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (bs, 1H), 7.32 (quartet,J=8 Hz, 2H), 7.15 (dd, J=8 Hz, 2 Hz, J_(moto)=0.8 Hz, 1H), 7.10-7.09 (m,1H), 6.68 (dd, J=8 Hz, 2.6 Hz, J_(moto)=0.8 Hz, 1H), 6.62 (d, J=8 Hz,1H), 3.89 (s, 3H), 3.65 (t, J=8 Hz, 2H), 3.13 (t, J=8 Hz, 2H).

Synthesis of 2-(5-(3-methoxyphenyl)indolin-1-yl)propanamide (vii): In around bottomed flask equipped with a nitrogen inlet and a refluxcondenser, a solution of 5-(3-methoxyphenyl)indoline (829 mg, 3.68 mmol)in 7 mL DMF was added. to the above solution, K₂CO₃ (1.39 g, 10.1 mmol)was added and the reaction mixture was stirred for 30 min. Potassiumiodide (70 mg, 0.42 mmol) and 2-bromopropionamide (616 mg, 1.71 mmol)were then added to the mixture and then heated at 110° C. or 2 hr. Thereaction was cooled to room temperature and then diluted with 40 mLwater. The aqueous mixture was extracted with CH₂Cl₂ (20 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated to yield brown oil as crude. The crude was purified with70% EtOAc in hexanes as eluent to give 1.024 g (94%) of the light brownoil as the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.39 (bs, 1H),7.34-7.31 (m, 2H), 7.13 (ddd, J=7.6, 1.6, 0.9 Hz, 1H), 7.08-7.07 (m,1H), 6.84 (ddd, J=8.2, 2.5, 0.8 Hz, 1H), 6.55 (d, J=8 Hz, 1H), 4.02(quartet, J=8 Hz, 1H), 3.87 (s, 3H), 3.56 (quartet, J=8 Hz, 1H), 3.50(quartet, J=8 Hz, 1H), 3.09 (t, J=8 Hz, 2H), 1.47 (d, J=8 Hz, 3H).

Synthesis of 2-(5-(3-methoxyphenyl)indolin-1-yl)propan-1-amine (viii):2-(5-(3-Methoxyphenyl)indolin-1-yl)propanamide (6.83 mmol, 2.024 g)dissolved in 1M BH₃.THF (20 mL) was added to a round bottomed flaskequipped with a nitrogen inlet and a reflux condenser. The reactionmixture was heated at reflux for 24 h. The reaction monitored by TLC.After the completion of reaction, the mixture was allowed to cool toroom temperature and then quenched slowly with MeOH. The solution wasconcentrated, dissolved in MeOH, and again concentrated. The resultingoil was diluted with ether and extracted twice with 1 N HCl. The aqueouswas treated with 2.5 N NaOH to adjust the pH>10 and extracted withchloroform. The combined chloroform extracts were dried over Na₂SO₄, andconcentrated to provide yellow oil as crude. The crude was columnchromatographed with 5% MeOH in CH₂Cl₂. The combined fractionscontaining the desired product were concentrated and then dried in vacuoyielding 820 mg (43%) of the product. ¹H NMR (400 MHz, CDCl₃) δ7.35-7.29 (m, 3H), 7.13 (dd, J=8 Hz, 2 Hz, J_(moto)=0.8 Hz, 1H),7.09-7.08 (m, 1H), 6.84 (dd, J=8 Hz, 3.6 Hz, J_(moto)=1.2 Hz, 1H), 6.55(d, J=8 Hz, 1H), 3.88 (s, 3H), 3.75-3.66 (m, 1H), 3.48-3.36 (m, 2H),3.06 (t, J=8 Hz, 2H), 2.94-2.78 (m, 2H), 1.12 (d, J=8 Hz, 3).

UANOX036(N-(2-(5-(3-methoxyphenyl)indolin-1-yl)propyl)-N,N-diethyl-1-sulfonamide)

UANOX036 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 7.35-7.33 (m, 3H), 7.14 (d, J=8 Hz, 1H), 7.08 (t,J=2.4 Hz, 1H), 6.84 (dd, J=7 Hz, 2.4 Hz, 1H), 6.56 (d, J=8 Hz, 1H), 4.60(bs, 1H), 3.963.87 (m, 1H), 3.88 (s, 3H), 3.45-3.36 (m, 2H), 3.33(quartet, J=6.8 Hz, 4H), 3.18-3.11 (m, 2H), 3.08-3.04 (m, 2H), 1.23 (t,J=8 Hz, 6H), 1.15 (d, J=6.8 Hz, 3H). HPLC-MS: Expected: 418 (MH⁺);Found: 418.

UANOX0254(N-(2-(5-(3methoxyphenyl)indolin-1-yl)propyl)-4-methylpiperazine-1-sulfonamide)

UANOX0254 was synthesized as per the procedure described for UANOX001.¹H NMR (400 MHz, CDCl₃) δ 7.36-7.32 (m, 2H), 7.30 (bs, 1H), 7.14 (dd,J=8 Hz, 2 Hz, J_(moto)=0.8 Hz, 1H), 7.09-7.08 (m, 1H), 6.82 (dd, J=7 Hz,2.4 Hz, 1H), 3.91 (t, J=8 Hz, 1H), 3.88 (s, 3H), 3.44-3.32 (m, 2H), 3.29(t, J=5 Hz, 4H), 3.22 (t, J=6.8 Hz, 2H), 3.08-3.04 (m, 2H), 2.51 (t, J=8Hz, 4H), 2.35 (s, 3H), 1.15 (d, J=8 Hz, 3H). HPLC-MS: Expected: 445(MH⁺); Found: 445.

To a round bottomed flask equipped with a nitrogen inlet and a magneticstir bar, a solution of indoline (1.07 g, 8.9 mmol, 1 mL) in 10 mLCH₂Cl₂ was added. to the above solution, Et₃N (0.90 g, 1.24 mmol) and2-bromoacetyl bromide (1.8 g, 0.78 mL, 8.9 mmol) were subsequentlyadded. The mixture was stirred at room temperature for overnight. Themixture was then concentrated. The residue was washed with water andthen with Et₂O, dried in vacuo yielding 2.12 g (99%) of the desiredproduct. ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8 Hz, 1H), 7.27 (d, J=8Hz, 1H), 7.19 (quartet, J=8 Hz, 1H), 7.09 (t, J=8 Hz, J_(moto)=1.2 Hz,1H), 4.25 (t, J=8 Hz, 2H), 4.15 (s, 2H), 3.23 (t, J=8 Hz, 2H), HPLC-MS:Expected: 364 (MH+); Found: 364.

Synthesis of 3-bromo-1-(indolin-1-yl)propan-1-one (intermediate ix_(b))

A solution of indoline (1.07 g, 8.9 mmol, 1 mL) in 10 mL CH₂Cl₂ wasadded to a round bottom flask equipped with a nitrogen inlet and amagnetic stir bar. To the above solution, Et₃N (0.90 g, 1.24 mmol) and3-bromopropanoyl chloride (1.53 g, 0.9 mL, 8.9 mmol) were subsequentlyadded. The mixture was stirred at room temperature for overnight. Themixture was then concentrated to give 2.92 g of crude product. Theresidue was washed with water and then washed with Et₂O, dried in vacuoyielding 2.4 g (100%) of crude which was used in the next step as it is.¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=8 Hz, 1H), 7.25 (d, J=8 Hz, 1H),7.18 (t, J=8 Hz, 1H), 7.04 (t, J=8 Hz, 1H), 4.16 (t, J=8 Hz, 2H), 3.74(t, J=8 Hz, 2H), 3.32 (t, J=8 Hz, 2H), 3.15 (t, J=8 Hz, 2H). HPLC-MS:Expected: 254 (MH⁺); Found: 254.

Synthesis oftert-butyl-4-(2-(indolin-1-yl)-2-oxoethyl)piperazine-1-carboxylate(intermediate x_(n))

In a round bottomed flask equipped with a nitrogen inlet and a magneticstir bar, the solution of 2-bromo-1-(indolin-1-yl)ethan-1-one (0.2 g0.83 mmol) in 5 mL CH₂Cl₂ was added. To the above solution, K₂CO₃ (0.29g, 2.10 mmol) and tert-butyl piperazine-1-carboxylate (0.31 g, 1.67mmol) were added. The mixture was stirred at room temperature forovernight and then washed with water (15 mL). The aqueous layer was thenextracted with CH₂Cl₂ (10 mL×3). The combined organic layers wereconcentrated and the crude was purified using column chromatography. Thedesired product was eluted with 2% MeOH in CH₂Cl₂ to yield 176 mg (61%)of the desired product. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=8 Hz, 1H),7.23-7.19 (m, 2H), 7.04 (t, J=8 Hz, 1H), 4.16 (t, J=8 Hz, 2H), 3.50 (t,J=8 Hz, 4H), 3.28 (s, 2H), 3.21 (t, J=8 Hz, 2H), 2.58 (t, J=8 Hz, 4H),1.61 (s, 9H). HPLC-MS: Expected: 346 (MH⁺); Found: 346.

Synthesis of tert-butyl4-(3-(indolin-1-yl)-3-oxopropyl)piperazine-1-carboxylate (intermediatex_(b))

Compound x_(b) was synthesized as per the procedure described forcompound x_(a). ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=8 Hz, 1H),7.24-7.20 (m, 2H), 7.04 (t, J=8 Hz, 1H), 4.10 (t, J=8 Hz, 2H), 3.47 (t,J=8 Hz, 4H), 3.24 (t, J=8 Hz, 2H), 2.88 (t, J=8 Hz, 2H), 2.67 (t, J=8Hz, 2H), 2.50 (t, J=8 Hz, 4H), 1.61 (s, 9H). HPLC-MS: Expected: 360(MH⁺); Found; 360.

Synthesis of 1-(indolin-1-yl)-2-(piperazin-1-yl)ethan-1-one(intermediate xi_(a))

In a round bottomed flask equipped with a nitrogen inlet and a magneticstir bar, a solution of 3-bromo-1-(indolin-1-yl)propan-1-one (1.1 g,4.58 mmol) in 25 mL CH₂Cl₂ was added. To the above solution, K₂CO₃ (1.56g, 11.30 mmol) and tert-butyl piperazine-1-carboxylate (1.70 g, 9.16mmol) were added. The mixture was stirred at room temperature forovernight and then dissolved in 35 mL water. The aqueous layer was thenextracted with CH₂Cl₂ (25 mL×3). The combined organic layers wereconcentrated to yield 1.86 g of crude. The crude was purified by columnchromatography and the desired product was eluted with 2% MeOH in CH₂Cl₂to yield 1.46 g (92%) of the desired product. ¹H NMR (400 MHz, CDCl₃) δ8.25 (d, J=8 Hz, 1H), 7.24-7.21 (m, 2H), 7.06 (t, J=8 Hz, 1H), 4.19 (t,J=8 Hz, 2H), 3.52 (t, J=8 Hz, 4H), 3.30 (s, 2H), 3.23 (t, J=8 Hz, 2H),2.59 (t, J=8 Hz, 4H). HPLC-MS: Expected: 246 (MH⁺); Found: 246.

Synthesis of 1-(indolin-1-yl)-3-(piperazin-1-yl)propan-1-one(intermediate xi_(b))

A solution of tert-butyl4-(3-(indolin-1-yl)-3-oxopropyl)piperazine-1-carboxylate (1.2 g, 3.34mmol) in 50 mL CH₂Cl₂ was added to a round bottomed flask equipped witha nitrogen inlet and a magnetic stir bar. To the above solution 12 mLCF₃COOH was added and the mixture was stirred at room temperature forovernight. The mixture was then adjusted to PH 11 with saturated aqueousNa₂CO₃ soln, and the layers were then separated. The aqueous layer wasthen extracted with CH₂Cl₂ (40 mL×3). The combined organic layers wereconcentrated to yield 0.78 g (90%) of the desired product. ¹H NMR (400MHz, Chloroform-d) δ 8.26 (d, J=8.2 Hz, 1H), 7.22 (t, J=7.9 Hz, 2H),7.12-6.96 (m, 1H), 4.21 (t, J=8.5 Hz, 2H), 3.23 (t, J=8.5 Hz, 2H),3.02-2.93 (m, 4H), 2.66-2.58 (m, 4H), 1.86-1.75 (m, 4H). HPLC-MS:Expected: 260 (MH⁺); Found: 260.

UANOX028(4-(2-(indolin-1-yl)-2-oxoethyl)-N,N-dimethylpiperazine-1-sulfonamide)

UANOX028 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ .821 (d, J=8 Hz, 1H), 7.20-7.17 (m, 2H), 7.04 (t,J=8 Hz, 1H), 4.11 (t, J=8 Hz, 2H), 3.33 (t, J=8 Hz, 4H), 3.29 (s, 2H),3.20 (t, J=8 Hz, 2H), 2.83 (s, 6H), 2.68 (t, J=8 Hz, 4H). HPLC-MS:Expected: 353 (MH⁺); Found: 353.

UANOX025(N,N-diethyl-4-(2-(indolin-1-yl)-2-oxoethyl)piperazine-1-sulfonamide)

UANOX025 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 8.21 (d, J=8 Hz, 1H), 7.21-7.17 (m, 2H), 7.03 (t,J=8 Hz, 1H), 4.13 (t, J=8 Hz, 2H), 3.30-3.25 (m, 10H), 3.20 (t, J=8 Hz,2H), 2.68 (t, J=8 Hz, 4H), 1.16 (t, J=7 Hz, 6H). HPLC-MS: Expected: 381(MH⁺); Found: 381.

UANOX026(1-(indolin-1-yl)-2-(4-(morpholinosulfonyl)piperazin-1yl)ethan-1-one)

UANOX026 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 8.24 (d, J=8 Hz, 1H), 7.24_7.21 (m, 2H), 7.06 (t,J=8 Hz, 1H), 4.14 (t, J=8 Hz, 2H), 3.75 (t, J=5 Hz, 4H), 3.39 (t, J=5Hz, 4H), 3.34 (s, 2H), 3.26 (t, J=8 Hz, 4H), 3.24 (t, J=8 Hz, 2H), 2.73(t, J=8 Hz, 4H). HPLC-MS: Expected: 395 (MH⁺); Found: 395.

UANOX027(1-(indolin-1-yl)-2-(4-(piperidin-1-ylsulfonyl)piperazin-1-yl)ethan-1-one)

UANOX027 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 8.23 (d, J=8 Hz, 1H), 7.22-7.18 (m, 2H), 7.04 (t,J=8 Hz, 1H), 4.13 (t, J=8 Hz, 2H), 3.34-3.30 (m, 6H), 2.69 (t, J=8 Hz,4H), 1.65-1.60 (m, 4H), 1.58-1.53 (m, 2H). HPLC-MS: Expected: 393 (MH⁺);Found: 393.

UANOX0192(1-(indolin-1-yl)-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethan-1-one)

In a round bottomed flask equipped with a nitrogen inlet and a magneticstir bar, the solution of 2-bromo-1-(indolin-1-yl)ethan-1-one (0.2 g,0.83 mmol) in 5 mL CH₂Cl₂ was added. To the above solution, K₂CO₃ (0.29g, 2.10 mmol) and 2-(piperazin-1-yl)pyrimidine (0.27 g, 1.64 mmol) werealso added. The mixture was stirred at room temperature for overnightand then washed with 15 mL water. The aqueous layer was then extractedwith CH₂Cl₂ (10 mL×3). The combined organic layers were concentrated togive crude product. The crude was purified using column chromatographywith 2% MeOH in CH₂Cl₂ to yield 120 mg (45%) of the desired product. Thefraction obtained was further purified using same condition to give 106mg of the pure and desired product. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d,J=4 Hz, 2H), 8.27 (d, J=8 Hz, 1H), 7.25-7.21 (m, 2H), 7.05 (t, J=8 Hz,1H), 6.50 (t, J=4 Hz, 1H), 4.21 (t, J=4 Hz, 2H), 3.92 (t, J=8 Hz, 4H),3.33 (S, 2H), 3.24 (t, J=8 Hz, 2H), 2.71 (t, J=8 Hz, 4H). HPLC-MS:Expected: 324 (MH⁺); Found:324.

UANOX032(4-(3-(indolin-1-yl)-3-oxopropyl)-N,N-dimethylpiperazine-1-sulfonamide)

UANOX032 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 8.22 (d, J=8 Hz, 1H), 7.23-7.19 (m, 2H), 7.04 (t,J=8 Hz, 1H), 4.09 (t, J=8 Hz, 2H), 3.30 (t, J=5 Hz, 4H), 3.23 (t, J=8Hz, 2H), 2.90 (t, J=8 Hz, 2H), 2.86 (s, 6H), 2.65 (t, J=5 Hz, 2H), 2.60(t, J=5 Hz, 4H). HPLC-MS: Expected: 367 (MH⁺); Found: 367.

UANOX029(N,N-diethyl-4-(3-(indolin-1-yl)-3-oxopropyl)piperazine-1-sulfonamide)

UANOX029 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 8.23 (d, J=8 Hz, 1H), 7.21-7.19 (m, 2H), 7.04 (t,J=8 Hz, 1H), 4.09 (t, J=8 Hz, 2H), 3.29 (quartet, J=8 Hz, 4H), 3.35-3.21(m, 6H), 2.89 (t, J=8 Hz, 2H), 2.65 (t, J=8 Hz, 2H), 2.60 (d, J=8 Hz,4H), 1.21 (t, J=8 Hz, 6H). HPLC-MS: Expected: 395 (MH⁺); Found: 395.

UANOX030(1-(indolin-1-yl)-3-(4-(morpholinosulfonyl)piperazin-1-yl)propan-1-one)

UANOX03 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 8.23 (d, J=8 Hz, 1H), 7.24-7.20 (m, 2H), 7.04 (t,J=8 Hz, 1H), 4.10 (t, J=8 Hz, 2H), 3.76-3.74 (m, 4H), 3.33 (t, J=8 Hz,4H), 3.27-3.22 (m, 6H), 2.91 (t, J=8 Hz, 2H), 2.66 (t, J=8 Hz, 2H), 2.61(t, J=5Hz, 4H). HPLC-MS: Expected: 409 (MH⁺); Found: 409.

UANOX031(1-(indolin-1-yl)-3-(4-(piperidin-1-ylsulfonyl)piperazin-1-yl)propan-1-one)

UANOX031 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃)δ 8.23 (d, J=8 Hz, 1H), 7.24-7.20 (m, 2H), 7.04 (t,J=8 Hz, 1H), 4.10 (t, J=8 Hz, 2H), 3.30 (t, J=5 Hz, 4H), 3.26-3.22 (m,6H), 2.91 (t, J=8 Hz, 2H), 2.67 (t, J=8 Hz, 2H), 2.61 (t, J=5 Hz, 4H),1.67-1.56 (m, 6H). HPLC-MS: Expected: 407 (MH⁺); Found: 407.

UANOX022(1-(indolin-1-yl)-3-(4-(pyrimidin-2-yl)piperazin-1-yl)propan-1-one)

UANOX022 was synthesized as per the procedure described for compound 50.¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=4 Hz, 2H), 8.24 (d, J=8 Hz, 1H),7.25-7.21 (m, 2H), 7.03 (t, J=8 Hz, 1H), 6.49 (t, J=4 Hz, 1H), 4.10 (t,J=8 Hz, 2H), 3.87 (t, J=8 Hz, 4H), 3.22 (t, J=8 Hz, 2H), 2.90 (t, J=8 H,2H), 2.70 (t, J=8 Hz, 2H), 2.60 (t, J=8 Hz, 4H). HPLC-MS: Expected: 388(MH⁺) and 339 (M+2); Found: 338 and 339.

UANOX023 (2-(cycloheptylamino)-1-(indolin-1-yl)ethan-1-one)

A solution of cycloheptanamine (1.87 mmol, 0.22 g, 0.24 mL) in 4 mL ofCH₃CN was added to a round bottomed flask equipped with a nitrogen inletand a magnetic stir bar. To the above solution,2-bromo-1-(indolin-1-yl)ethan-1-one (0.15 g, 0.624 mmol) in 2 mL CH₃CNwas added dropwise. The mixture was stirred at room temperature forovernight and then concentrated to give crude product. The product waspurified using column chromatography with 2-5% MeOH in CH₂Cl₂ solvent toyield 110 mg (65%) of the desired product. The compound was re-purifiedusing the same method above to give 68 mg (40%) of the pure compound asindicated by HPLC. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=8 Hz, 1H),7.23-7.19 (m, 2H), 7.02 (t, J=8 Hz, 1H), 4.04 (t, J=8 Hz, 2H), 3.52 (s,2H), 3.24 (t, J=8 Hz, 2H), 2.70 (septet, 4 Hz, 1H), 1.94-1.86 (m, 2H),1.74-1.67 (m, 2H), 1.62-1.53 (m, 4H), 1.51-1.43 (m, 4H). HPLC-MS:Expected: 274 (M+2); Found: 274.

UANOX024 (3-(cycloheptylamino)-1-(indolin-1-yl)propan-1-one)

UANOX024 was synthesized as per the procedure described for compoundUANOX023. ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8 Hz, 1H), 7.23-7.19 (m,2H), 7.08 (t, J=8 Hz, 1H), 4.08 (t, J=8 Hz, 2H), 3.41 (t, J=8 Hz, 2H),3.36-3.31 (m, 1H), 3.30 (quartet, J=4 Hz, 2H), 3.20 (t, 8 Hz, 2H),2.32-2.25 (m, 2H), 1.97-1.90 (m, 2H), 1.89-1.81 (m, 2H), 1.64-1.61 (m,4H), 1.59-1.48 (m, 2H). HPLC-MS: Expected: 288 (M+2); Found: 228 and339.

Synthesis of 1-(4-nitrophenyl)indoline (xii): a microwave vial wascharged with the 4-bromonitrobenzene (2.16 g, 10.69 mmol), indoline(1.28 g, 10.70 mmol), and Pd₂(dba)₃ (0.059 mmol, 53 mg), K₂CO₃ (42.69mmol, 5.9 g) and DMF (5 mL). The mixture was heated at 140° C. for 30min at medium power in a heritage initiator. The reaction mixture waspoured into to water and the aqueous was extracted with CH₂Cl₂ (×3). Thecombined organic layers were dried over Na₂SO₄, filtered, rotaryevaporated and then dried in vacuo. the crude was loaded onto a flashsilica gel column which was eluted with hexane-EtOAc (4:1) to give 2.27g (88%) of the purified product as orange red solid. ¹H NMR (400 MHz,CDCl₃) δ 8.24 (d, J=8 Hz, 2H), 7.37 (d, J=8 Hz, 1H), 7.30-7.28 (m, 2H),7.24 (d, J=8 Hz, 2H), 6.96 (t, J=7.4 Hz, 1H), 4.10 (t, J=8 Hz, 2H), 3.24(t, J=8 Hz, 2H).

Synthesis of 4-(indolin-1-yl)aniline (xiii): the solution of1-(4-nitrophenyl)indoline (1.43 g, 9.44 mmol) in 15 mL EtOH was added toa round bottomed flask equipped with a nitrogen inlet and a magneticstir bar. To the above solution, SnCl₂.2H₂O (3.35 g, 14.85 mmol) wasadded and then the mixture was stirred at 70° C. overnight. To themixture was added 4 N NaOH and the aqueous was extracted with EtOAc(×3). The combined organic layers were dried over anhydrous Na₂SO₄,concentrated and then dried in vacuo yielding brownish orange oil ascrude. The crude was column chromatographed with 20% EtOAc in Hexanesyielding 630 mg (50%) of the pure and desired compound as purple solid.¹H NMR (400 MHz, CDCl₃) δ 7.16 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 2H),7.05 (t, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 6.76-6.69 (m, 3H), 3.99-3.77(m, 2H), 3.13 (t, J=8 Hz, 2H). HPLC-MS: Expected: 210 (M(⁺; Found: 320.

UANOX038 (N-(N,N-diethylaminosulfonyl)-4-(indolin-1-yl)aniline)

UANOX038 was synthesized as per the procedure described for UANOX001. ¹HNMR (400 MHz, CDCl₃) δ 7.20-7.18 (m, 5H), 7.10-7.09 (m, 2H), 6.80-6.76(m, 1H), 3.95 (t, J=8 Hz, 2H), 3.30 (t, J=7 Hz, 2H), 3.16 (t, J=8 Hz,2H), 1.13 (t, J=7 Hz, 2H). HPLC_MS: Expected: 345 (MH⁺); Found: 345.

Synthesis of tert-butyl 4-(2-bromomethyl)piperazine-1-carboxylate (xvii)

In a round bottom flask equipped with N₂ inlet, a magentic stir bar andan additional funnel, N-Box-4-(2-hydroxyethyl) piperazine (xvi) (1 g,4.34 mmol), PPh₃ (1.23 g, 4.7 mmol) CH₂Cl₂ (10 mL) was added. to theabove mixture, a solution of carbon tetrabromide (1.58 g., 4.7 mmol) in10 mL of CH₂Cl₂ was added dropwise over 2 h at 0° C. The mixture wasstirred at room temperature for 20 h. the organic phase was evaporatedto obtain an oil that was purified by flash chromatography (ethylacetate/hexanes 2/8) to afford the desired product as an oily compoundthat slowly crystallized on storage (1.32, yield 100%). ¹H NMR (400 MHz,Chloroform-d) δ 3.51-3.30 (m, 6H), 2.82-2.67 (m, 2H), 2.50-2.23 (m, 4H),1.43 (s, 9H). Synthesized according to the procedure reported in J. Med.Chem, 2004, 47, 3, 711-719 and PCT Int. Appl. 2013064919, 10 May 2013.

Synthesis of tert-butyl4-(2-(indolin-1-yl)ethyl)piperazine-1-carboxylate (xvii)

Into a round bottomed flask equipped with a nitrogen inlet and a refluxcondense, the solution of Indoline (0.55 g, 4.62 mmol, 0.52 mL) in 5 mLDMF was added. To the above solution, K₂CO₃ (1.25 g, 9.04 mmol) wasadded and then the mixture was stirred for 30 min. To the above mixture,tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (1.35 g, 4.60 mmol,1 eq) were then added to the mixture. The mixture was then heated at110° C. or 2 hr. The mixture was then diluted with DI water, extractedwith CH₂Cl₂ (×3). The combined organic layers were dried over Na₂SO₄anhydrous, concentrated and then dried in vacuo yielding 17 g of crude.The oily crude was column chromatographed with 50-70% EtOAc in Hexanesto give 1.3 g (87%) of the pure and desired compound. ¹H NMR (400 MHz,Chloroform-d) δ 7.14-6.96 (m, 2H), 6.64 (d, J=8.2 Hz, 1H), 6.46 (d,J=7.6 Hz, 1H), 3.43 (t, J=4.9 Hz, 4H), 3.38 (t, J=8.3 Hz, 2H), 3.22 (t,J=8.3 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.46 (t,J=5.0 Hz, 4H), 1.44 (s, 9H). HPLC-MS: Expected: 333 (M+2)⁺; Found: 333.

Synthesis of 1-(2-(piperazin-1-yl)ethyl)indoline (xix)

Into a round bottomed flask equipped with a nitrogen inlet and amagnetic stir bar, the solution of tert-butyl4-(2-(indolin-1-yl)ethyl)piperazine-1-carboxylate (1.3 g, 3.92 mmol) in60 mL CH₂Cl₂ was added. to the above solution 17 mL of CF₃COOH was addedand the mixture was stirred at room temperature for overnight. Thereaction was monitored with TLC. The mixture was rotary evaporated,dissolved in water and then basified to pH 11 with sat aqueous Na₂CO₃soln, poured into a separatory funnel and the layers were separated. Theaqueous layer was then extracted with CH₂Cl₂ (×3). The combined organiclayers were concentrated using rotary evaporator and then dried in vacuoyielding 930 mg (100%) of the desired product. ¹H NMR (400 MHz,Chloroform-d) δ 7.06-7.02 (m, 2H), 6.62 (t, J=7.4 Hz, 1H), 6.47 (d,J=8.0 Hz, 1H), 3.38 (t, J=8.3 Hz, 2H), 3.22 (t, J=7.8 Hz, 2H), 3.00-2.83(m, 6H), 2.58 (t, J=7.1 Hz, 2H), 2.55-2.43 (m, 4H). HPLC-MS: Expected:232 (MH)⁺; Found: 232

UANOX062(1-(2-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl)indoline)

Into a 25 mL round bottomed flask equipped with a nitrogen inlet and amagnetic stir bar, 154 mg (0.67 mmol) of1-(2-(piperazin-1-yl)ethyl)indoline, 210 mg (0.81 mmol) of4-(trifluoromethoxy)benzenesulfonyl chloride, 0.19 mL (1.36 mmol) oftriethylamine and 5 mL of CH₂Cl₂ were added. The mixture was stirredvigorously at room temperature for 18 h. To the mixture, DI water wasadded and then the mixture was transferred into a separatory funnel andthe layers were separated. The aqueous layer was then extracted withCH₂Cl₂ (×3). The combined organic extracts were dried over anhydrousNa₂SO₄, the drying agent was removed by filtration and the filtrate wasconcentrated by rotary evaporation. The residue was further dried invacuo to give light yellow oil as crude. The crude was then purified byprep TLC with 60% ethyl acetate in hexanes to give 185 mg (61%) of thepure and desired product as white solid. ¹H NMR (400 MHz, Chloroform-d)δ 7.84 (d, J=9.0 Hz, 2H), 7.41-7.37 (m, 2H), 7.12-7.00 (m, 2H), 6.66(td, J=7.5, 1.0 Hz, 1H), 6.45 (d, J=7.8 Hz, 1H), 3.36 (t, J=8 Hz, 2H),3.19 (t, J=8 Hz, 2H), 3.10 (t, J=8 Hz, 4H), 2.97 (t, J=8 Hz, 2H),2.71-2.60 (m, 6H). HPLC-MS: Expected: 456 (MH)⁺; Found: 456 and 454.

UAONOX063 (Synthesis ofN,N-diethyl-4-(2-(indolin-1yl)ethyl)piperazine-1-sulfonamide)

UANOX063 was synthesized as per the procedure described for UANOX062, ¹HNMR (400 MHz, Chloroform-d) δ 7.10-7.06 (m, 2H), 6.67 (td, J=7.5, 1.0Hz, 1Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 3.42 (t, J=8.4 Hz, 2H), 3.30 (q,J=7.0 Hz, 4H), 3.27-3.22 (m, 6H), 2.99 (t, J=8.3 Hz, 2H), 2.66 (t, J=8.3Hz, 2H), 2.63-2.59 (m, 4H), 1.21 (t, J=7.1 Hz, 6H), HPLC-MS: Expected:367 (MH)⁺: Found: 367.

UANOX064(1-(2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl)indolin)

UANOX064 was synthesized as per the procedure described for UANOX062. ¹HNMR (400 MHz, Chloroform-d) δ 7.80 (dd, J=9.0, 5.1 Hz, 2H), 7.24 (dd,J=9.0, 8.3 Hz, 2H), 7.10-7.02 (m, 2H), 6.66 (td, J=7.4, 1.0 Hz, 1H),6.45 (d, J=7.8 Hz, 1H), 3.36 (t, J=8.4 Hz, 2H), 3.19 (, J=8.4 Hz, 2H),3.12-3.06 (m, 4H), 2.96 (t, J=8.3 Hz, 2), 2.70-2.60 (m, 6H). HPLC-MS:Expected: 390 (MH)⁺; Found: 390.

UANOX066 (Synthesis of1-(2-(4-(benzo[d][1,3]dioxol-5-ylsulfonyl)piperazin-1-yl)ethyl)indoline)

UANOX066 was synthesized as per the procedure described for UANOX062. ¹HNMR (400 MHz, Chloroform-d) δ 7.11-7.04 (m, 2H), 6.67 (td, J=7.3, 1.0Hz, 1H), 6.51 (d, J=7.4 Hz, 1H), 3.42 (t, J=8.4 Hz, 2H), 3.31-3.26 (m,6H), 3.23 (q, J=7.1 Hz, 4H), 2.99 (t, J=8.4 Hz, 2H), 2.66 (t, J=8.4 Hz,2H), 2.60-2.53 (m, 4H), 1.15 (t, J=7.1 Hz, 6H. HPLC-MS: Expected: 331(MH)⁺; Found: 331

UANOX067 (Synthesis of1-(2-(4-(2-fluorobenzyl)piperazin-1-yl)ethyl)indoline)

In a round bottomed flask equipped with a nitrogen inlet and a magneticstir bar, 2-fluorobenzaldehyde (84 mg, 0.67 mmol),1-(2-(piperazin-1-yl)ethyl)indoline (154 mg 0.67 mmol) and CH₂Cl₂ (5 mL)were added. To the above mixture AcOH (38 μL, 0.67 mmol) was added. Thereactant was stirred for 1 hour at room temperature. To the mixtureNa(OAc)₃BH (426 mg, 2.01 mmol) was added in portion over a period of 2hours. The reaction mixture was allowed to stir overnight at roomtemperature. The reaction mixture was poured into H₂O and the aqueouswas extracted with CH₂Cl₂ (×3). The organic layer was dried over Na₂SO₄,filtered and then rotary evaporated. The crude was purified bypreparatory TLC with 10% MeOH in CH₂Cl₂ to give 208 mg of the desiredproduct. the product was repurified using same condition as above togive 81 mg (36%) of the pure and desired compound as amber color oil. ¹HNMR (400 MHz, Chloroform-d) δ 7.39 (td, J=7.5, 1.8 Hz, 1H), 7.31-7.23(m, 1H), 7.13 (td, J=7.5, 1.2 Hz, 1H), 7.10-7.02 (m, 3H), 6.67 (td,J=7.4, 1.0 Hz, 1H), 6.50 (d, J=9.1 Hz, 1H), 3.69 (d, J=1.3 Hz, 2H), 3.40(t, J=8.3 Hz, 2H), 3.29 (t, J=8.3 Hz, 2H), 2.98 (t, J=8.3 Hz, 2H), 2.73(t, J=8.3 Hz, 4H), 2.67-2.59 (m, 4H), 2.10-2.06 (m, 2H). HPLC-MS:Expected: 340 (MH)⁺; Found: 340.

Nox 4 Mediates Fibrotic Responses to Lung Injury

The NADPH-oxidase (Nox) enzymes are an evolutionarily conserved genefamily that that is most consistently linked to host defense mechanisms,including lung fibrosis (Bernard K et al., Antioxidants & redoxsignaling 20: 2838-2853, 2014; Thannickal V J Zhou Y, Gaggar A, andDuncan S R. Fibrosis: ultimate and proximate causes. The Journal ofclinical investigation 124: 4673-4677, 2014). The role of Nox4 ininjury-induced fibrosis was evaluated using a murine model of lunginjury. In this animal model, intra-tracheal instillation of thechemotherapeutic agent, blcomycin, induces epithelium injury that leadsto peak fibrosis 2-3 weeks post-injury (Hecker L et al., NADPH oxidase-4mediates myofibroblast activation and fibrogenic responses to lunginjury. Nature medicine 15: 1077-1081, 2009; Izbicki G et al., Timecourse of blcomycin-induced lung fibrosis. International journal ofexperimental pathology 83: 111-119, 2002). Nox4 is induced in atime-dependent manner, increasing from day 7 up to day 28, supporting atemporal relationship between Nox4 expression, myofibroblast activation,and fibrosis following lung injury (Nature medicine 15: 1077-1081,2009). In contrast, the Nox2 isoform (predominantly expressed inphagocytic cells) increases on day 7 (peak inflammatory phase) andreturns to baseline levels at later time-points when inflammatoryresponses subside (Nature medicine 15: 1077-1081, 2009).

Nox4 is Upregulated in the Lungs of Human IPF Patients

Among the seven members of the Nox family, Nox4 has now been implicatedin a variety of fibrotic diseases, including the liver (Aoyama T et al.,Hepatology 56: 2316-2327, 2012; Bettaieb A et al., Gastroenterology 149:468-480 c 410, 2015; Sancho P et al., PloS one 7: c45285, 2012), skin(Spadoni T et al., Arthritis & rheumatology 67: 1611-1622, 2015), kidney(Barnes J L et al., Kidney international 79: 944-956, 2011; Sedeek M etal., American journal of physiology Renal physiology 299: F1348-1358,2010), heart (Ago T et al., Aging 2: 1012-1016, 2010; Kuroda J et al.,Proceedings of the National Academy of Sciences of the United States ofAmerica 107: 15565-15570, 2010), and lung (Griffith B et al.,Antioxidants & redox signaling 11: 2505-2516, 2009; Harrison C et al.,Nat Rev Drug Discov 8: 773-773, 2009; Hecker L. et al., Sciencetranslational medicine 6: 23 Ira247, 2014; Nature medicine 15:1077-1081, 2009). It has been demonstrated that Nox4 is upregulated inlung myofibroblasts of human IPF patients (Amara N et al., Thorax 65:733-738, 2019; Science translational medicine 6: 23Ira247, 2014).

Therapeutic targeting of Nox4 inhibits the development of fibrosis andresults in a reversal of established/persistent fibrosis in mice.

While is has been shown that genetic targeting of Nox4 ameliorates thedevelopment of injury-induced lung fibrosis in young mice (Naturemedicine 15: 1077-1081, 2009). It has also been demonstrated thatgenetic knockdown of Nox4 (via intra-tracheal delivery of Nox4-siRNA tothe lungs of injured mice) in an animal model of persistent lungfibrosis led to a reversal of established fibrosis (Sciencetranslational medicine 6: 231ra247, 2014). It was later validated bysimilar findings using mice with genetic deletion of Nox4 (Carnescchi Set al., Antioxid Redox Signal 15: 607-619, 2011). Overall, these studiesdemonstrate a critical role for Nox4 in mediating lung fibrosis. sincethe initial discovery that Nox4 mediates lung tissue fibrosis (NatureMedicine, 2009), Nox 4 has been implicated in fibrotic disease ofvarious organ systems (liver, skin, kidney, and cardiac). Nox4 is nowconsidered to be among the most promising therapeutic targets forfibrotic disease (Nat Rev Drug Discov 8: 773-773, 2009; Liepelt A etal., Annals of translational medicine 3: S13, 2015). However, noselective Nox4 inhibitors are clinically available.

Efficacy of Analogs for Inhibition of Nox4-Dependent H₂O₂

A high-throughput screening (HTS) assay was established for Nox4inhibition, utilizing HEK293 cells that stably over-express Nox4(HEK/Nox4 cells), which generate high levels of H₂O₂ (Cheng G et al.,Gene: 2001, p. 131-140). Over 30,000 compounds have been screened andmedicinal chemistry efforts have led to the synthesis of numerousanalogs and the identification of a chemically distinct series ofselective Nox4 inhibitors. Table 1 shows dose-dependent activity ofvarious analogs synthesized. FIG. 1A shows a subset of these analogsversus vehicle and DPI (a positive control, as DPI inhibits all Noxactivity). Treatment with UAVNox048 or UANox034 led to a dose-dependentdecrease in H₂O₂ generation by HEK/Nox4 cells, as measured by Amplex Redassay (FIG. 1A). IC-50 was evaluated for UANox048 (FIG. 1B).

TABLE 1 Efficacy for inhibition of Nox4-dependent H₂O₂. HEK cells stablytransfected to overexpress Nox4 were treated with test compounds andsynthesized analogs in DMSO and incubated for 1 h. H₂O₂ production wasevaluated by Amplex Red assay. Values represent means and SD of H₂O₂production after treatment with 1, 5, and 10 μM (final concentration)test compounds and synthesized analogs. H₂O₂ production reportedrelative to vehicle control; n = 3-10/group. Final concentration (μM) 15 10 Compound Name Mean SD Mean SD Mean SD DMSO 1.000 0.050 (Vehiclecontrol) UANOX001 0.995 0.060 1.063 0.030 1.032 0.011 UANOX002 0.9860.067 1.061 0.035 1.015 0.037 UANOX003 1.008 0.134 1.029 0.015 1.0280.018 UANOX004 0.994 0.029 1.007 0.070 0.882 0.167 UANOX006 0.822 0.1050.825 0.108 0.741 0.107 UANOX007 1.026 0.028 0.916 0.037 0.908 0.016UANOX008 0.984 0.065 0.779 0.113 0.678 0.091 UANOX011 0.980 0.080 0.9790.019 0.956 0.008 UANOX012 0.960 0.003 0.950 0.040 0.857 0.073 UANOX0131.006 0.041 0.921 0.060 0.881 0.020 UANOX018 1.101 0.056 1.027 0.0371.002 0.068 UANOX019 0.915 0.153 0.814 0.185 0.741 0.135 UANOX020 0.7370.089 0.870 0.110 0.866 0.111 UANOX021 0.742 0.054 0.876 0.021 0.7910.040 UANOX022 1.106 0.075 1.069 0.055 1.103 0.030 UANOX023 0.984 0.0621.077 0.062 1.003 0.043 UANOX025 1.071 0.015 1.131 0.020 1.124 0.065UANOX026 0.906 0.232 1.059 0.074 1.011 0.143 UANOX027 1.128 0.017 1.1310.012 1.124 0.027 UANOX028 1.081 0.051 1.123 0.007 1.111 0.038 UANOX0291.125 0.035 1.117 0.021 1.096 0.058 UANOX030 1.080 0.034 1.084 0.0271.037 0.012 UANOX031 1.111 0.019 1.106 0.040 0.997 0.045 UANOX032 1.1180.036 1.091 0.066 1.052 0.048 UANOX033 1.004 0.052 0.912 0.148 0.8670.034 UANOX034 0.959 0.032 0.803 0.039 0.706 0.017 UANOX036 1.018 0.0370.832 0.027 0.747 0.016 UANOX037 0.972 0.029 0.793 0.052 0.773 0.035UANOX038 0.925 0.150 0.800 0.125 0.635 0.226 UANOX048 0.893 0.020 0.7650.031 0.693 0.023 UANOX049 0.871 0.028 0.784 0.016 0.714 0.019 UANOX0540.902 0.038 0.876 0.013 0.824 0.017 UANOX055 0.902 0.019 0.908 0.0060.868 0.028 UANOX056 0.959 0.025 0.884 0.033 0.834 0.023 UANOX062 0.8870.066 0.758 0.040 0.664 0.052 UANOX063 0.902 0.063 0.719 0.031 0.6650.022 UANOX064 0.863 0.040 0.757 0.022 0.724 0.033 UANOX066 0.953 0.0200.722 0.037 0.731 0.021 UANOX067 0.939 0.040 0.912 0.016 0.851 0.014UANOX070 0.914 0.025 0.779 0.024 0.693 0.003 UANOX071 0.908 0.010 0.8560.001 0.770 0.012 UANOX073 0.942 0.094 0.759 0.029 0.744 0.057 UANOX0750.823 0.057 0.721 0.055 0.677 0.042 UANOX076 0.832 0.025 0.720 0.0310.662 0.026 UANOX079 0.896 0.007 0.651 0.016 0.584 0.031 UANOX080 0.8550.039 0.601 0.044 0.491 0.028 UANOX081 0.888 0.056 0.670 0.018 0.5580.060 UANOX082 0.908 0.058 0.707 0.032 0.606 0.038 UANOX083 0.823 0.0830.730 0.016 0.665 0.007 UANOX084 0.903 0.038 0.775 0.057 0.675 0.023UANOX085 0.927 0.056 0.835 0.018 0.736 0.024 UANOX086 0.907 0.046 0.8160.013 0.714 0.006 UANOX087 0.997 0.036 0.883 0.014 0.741 0.008 UANOX0881.023 0.047 0.903 0.012 0.796 0.019 UANOX089 1.013 0.019 0.836 0.0560.701 0.022 UANOX090 1.045 0.017 0.887 0.042 0.745 0.009 UANOX0254 0.8780.126 0.880 0.025 0.763 0.081 UANOX0192 0.964 0.033 1.108 0.044 1.0800.023

HEK cells stably transfected to overexpress Nox4 were treated withvarying concentrations of test compounds, DPI (all-Nox inhibitorpositive control), or DMSO (vehicle control) and incubated for 1 h (FIG.1). (FIG. 1A) H₂O₂ presence was evaluated by Amplex Red assay. (FIG. 1B)IC₅₀ was evaluated for UANox048 in HEK/Nox4 cells and was thendetermined to be 4.8 μM. Values represent means±SEM; n=4. P values werecalculated by student's two-tailed t test. *p<0.05, **p<0.01,***p<0.001.

Compounds Pass False-Positive Testing

Screening was performed to rule out false positives (UANox048 does notdemonstrate scavenger activity (FIG. 2A), does not exhibit assayinterference (via inhibition of HRP activity) (FIG. 2B), and does notaffect cellular viability (FIG. 2C).

UANox048, DMSO (vehicle control), or catalase (known H₂O₂ scavengerpositive control) was added to a cell-free assay containing exogenousH₂O₂ (5 mM) and scavenger activity of H₂O₂ was assessed by (FIG. 2A)Amplex Red assay and (FIG. 2B) ROS-Glo assay (an HRP-free assay systemto rule out assay interference). (FIG. 2C) HEK cells stably transfectedto overexpress Nox4 were treated with UANox048, digitonin (an inducer ofcell death), or DMSO (vehicle control) and incubated for 1 h. Cellularviability was evaluated by CellTiter-Glo Assay. Values representmeans±SEM; n=4; P values were calculated by student's two-tailed t test.*p<0.05, **p<0.01, ***p<0.001.

Compounds are Highly Selective for Nox4-Dependent H₂O₂

There are no clinically-available selective Nox4 inhibitors. Screeningassays to evaluate selectivity against Nox1 and Nox2 were developed inan effort to identify highly selective inhibitors of Nox4, with lowselectivity for closely-related Nox homologs. Importantly, analogs showlittle to no inhibition of Nox2- and Nox1-dependent H₂O₂ (FIG. 3).Additionally, analogs do not inhibit Nox-independent mechanisms of H₂O₂production, as measured by impact on xanthine oxidase (XO)-dependentH₂O₂ generation. These data support the identification of small-moleculeinhibitors that are highly selective for Nox4.

Caco-2 cells were co-treated with Calcitriol (1 μM, 18 h, to induceNox1-dependent H₂O₂ generation) and test compounds, DPI (all-Noxinhibitor positive control), or DMSO (vehicle control). H₂O₂ productionwas evaluated by Amplex Red assay (FIG. 3A). RAW 264.7 cells wereco-treated with PMA (20 μM, 2 h, to induce Nox2-dependent H₂O₂generation) and test compounds, DPI (all-Nox inhibitor), or DMSO(vehicle). Nox2-dependent H₂O₂ was evaluated by Amplex Red assay (FIG.3B). XO-dependent H₂O₂ production was initiated in the presence of testcompounds or vehicle control (DMSO). The reaction was incubated for 30 mand H₂O₂ presence was quantified by Amplex Red assay (FIG. 3C). Valuesrepresent means±SEM; n=3; P values were calculated by student'stwo-tailed t test. *p<0.05, **p<0.01, ***p<0.001.

Compounds Demonstrate Inhibition of Disease-Relevant Cellular Phenotypesin Human Lung Fibroblasts

It has been demonstrated that TGF-β1 (a cytokine known to be highlyexpressed in fibrotic diseases) leads to the induction of Nox4-dependentH₂O₂, which mediates critical pro-fibrotic lung myofibroblastphenotypes, including differentiation, contraction, and ECM generation(Nature medicine 15: 1077-1081, 2009). Whole-genome Affymetrix analysisin human lung fibroblasts revealed that in response to TGF-β1, Nox4 wasamong the most highly induced genes in the human genome (Nature medicine15: 1077-1081, 2009). The inducibility of Nox4-dependent H₂O₂ by TGF-β1is a highly specific and unique function of Nox4 (Martyn K D et al.,Cellular signalling 18: 69-82, 2006; Serrander L et al., The Biochemicaljournal 406: 105-114, 2007; von Lohneysen K et al., The Journal ofbiological chemistry 287: 8737-8745, 2012; von Lohneysen K et al., TheJournal of biological chemistry 283: 35273-35282, 2008; von Lohneysen Ket al., Molecular and cellular biology 30: 961-975, 2010); no other Noxfamily gene members are affected at the mRNA level (Nature medicine 15:1077-1081, 2009). This unique feature of Nox4 has been exploited inscreening efforts to validate lead drug candidates. Analogs demonstratedhigh efficacy for inhibition of TGF-β-induced Nox4-dependent H₂O₂ inhuman lung fibroblasts (FIG. 4).

Analogs Inhibit TGF-β1-Induced Nox4-Dependent H₂O₂ in Human LungFibroblasts

Human lung fibroblasts (IMR90 cells) were serum starved for 16 h, thenstimulated with/without TGF-β1 (2 ng/ml) for 12 h. Cells were thentreated with test compounds, DPI (all-Nox inhibitor positive control),or DMSO (vehicle control) and incubated for an additional 4 h. H₂O₂ wasevaluated by Amplex Red Assay (FIG. 4). values represent means±SEM; n=3;*P<0.05 using Student's two-tailed t. *p<0.05, **p<0.01, ***p<0.001.

TGF-β1-induced Nox4-dependent H₂O₂ mediates fibroblast-to-myofibroblastdifferentiation, as characterized by the synthesis of α-smooth muscleactin (αSMA). These key effector cells play a central role in fibrotic“scar” generation, as they are contractile cells responsible for thesynthesis of extracellular matrix (ECM) components. The accumulation ofαSMA-expressing myofibroblast cells is a key pathological hallmark offibrotic disease (Desmouliere A et al., The American journal ofpathology 146, 56-66, 1995). The compounds were evaluated for theirability to inhibit fibroblasts-to-myofibroblast differentiation. Analogseffectively inhibit TGF-β-induced Nox4-dependent myofibroblastdifferentiation in human lung fibroblasts (FIG. 5). together, these dataindicate that analogs demonstrate the ability to inhibit keypro-fibrotic cellular phenotypes in human lung fibroblasts.

Analogs Inhibit TGF-β1-Induced Fibroblast-to-MyofibroblastDifferentiation

Human lung fibroblasts (IMR90 cells) were serum starved for 16 h, thenstimulated with/without TGF-β1 (2 ng/ml) and co-treated with testcompounds, DPI (all-Nox inhibitor positive control), or DMSO (vehiclecontrol) and incubated for 48 h. αSMA presence was evaluated byWestern-immunoblotting (FIG. 5A), and densitometric analyses (FIG. 5B).Values represent means±SEM; n=4; *P<0.05 using Student's two-tailedt-test. *p=0.05, **p<0.01, ***p<0.001.

Biophysical Characterization and Microscopy of Analogs

Studies were performed on the biophysical characterization of selectedanalogs, to demonstrate feasibility of an essential requirement aimed atguiding rational formulation design and ensuring reproducibility (i.e.,quality control) of compound integrity during scale-up, manufacture, andstorage. Differential scanning calorimetry (DSC) was used, a highlysensitive thermos-analytical technique to quantify the thermotropicproperties and phase transitions of drug candidates. UANox048 was foundto be highly stable, with a relatively high solid-to-liquid meltingphase transition; T_(onset) 89.72±0.22 (° C.), T_(peak)92.3±0.05 (°C.),enthalpy 64.87±21.39 (J/g) measuring the energetic during thesolid-to-liquid phase transition (FIG. 6A). This is important from apharmaceutical standpoint, as these data indicate that UANOX048 ishighly stable at both room and body temperatures (32-37° C.; drugmanufacture/processing and delivery temperatures). X-ray powderdiffraction (XRPD) is a non-destructive material science “gold standard”method for measuring the degree of long-range molecular order in thepowder. This is critical for solid-state characterization, where drugcandidates yield a unique pattern for any given crystalline phase; thisprovides a ‘molecular fingerprint’ for crystallinity identification.XRPD of UANox048 demonstrates a unique molecular signature, which isconsistent between batches of UANOX048 synthesized at different times indifferent quantities (FIG. 6B). Attenuated Total Reflection FourierTransform Infrared (ATR-FTIR) Spectroscopy is a non-destructivemolecular identification tool based on the absorption of infrared lightby vibrational transitions in covalent bonds. This provides a ‘molecularfingerprint’ for chemical identification. ATR-FTIR permits finediscrimination between like materials and/or batch-to-batch qualityverification; it is used to identify active pharmaceutical ingredients(API). ATR-FTIR spectroscopy reveals a consistent molecular fingerprintof UANox048 from two different batches, synthesized at different times.Together, XRPD and ATR-FTIR results demonstrate proof-of-concept andfeasibility of successful and consistent UANox048 scale-up. ScanningElectron Microscopy (SEM) with Energy Dispersive X-ray (EDX) is used tovisualize the synthesized particles in their native solid-state andquantify important particle properties which directly influenceformulation, including surface structure, particle morphology and size,and particle size range distribution. SEM of UANox048 indicates asurface structure that is typical of small molecular weight drugs withcrystalline properties. Confocal Raman Microspectroscopy is anon-destructive analytical tool that is used to evaluate the spatialdistribution of chemical components within a formulation; this permitscharacterization of formulation homogeneity and detection of foreignparticulate contaminants. This critical molecular identification tool isroutinely used to determine patent infringements. Confocal Ramanmicrospectroscopy of UANox048 demonstrates a unique molecularfingerprint of its chemical identity.

Analogs Demonstrate Favorable In Vitro ADME Characteristics for OralFormulation/Delivery

In vitro absorption, distribution, metabolism, and excretion (ADME) wereperformed on selected analogs to assess their potential for continuedpre-clinical development. UANox048 analog has favorablepharmacokinetic/pharmacodynamics properties, including a low molecularweight (384.4 g/mol), calculated log D value (4.07), and polar surfacearea (57.8 Å²). The compounds were tested for cellular permeability andP-glycoprotein efflux susceptibility (P-gp efflux). UANox048demonstrates effective Caco-2 permeability properties (high), and noP-gp efflux. P-gp efflux was calculated by comparing permeabilitythrough Caco-2 monolayers in both the apical-to-basolateral andbasolateral-to-apical directions. Permeability for Caco-2 cells wasdetermined by the lucifer yellow monolayer integrity test. Caco-2 cellswere incubated with UANox048 (5 μM, 2 h) and flux of lucifer yellowacross cell monolayers was determined by LC-MS/MS using electrosprayionization. Molecular weight, log D, and polar surface area calculationswere performed with ChemDraw software. These data demonstrate favorablecharacteristics for oral formulation/delivery UANox048 indicating anopportunity for further development.

The foregoing discussion of the invention has been presented forpurposes of illustration and description. The foregoing is not intendedto limit the invention to the form or forms disclosed herein. Althoughthe description of the invention has included description of one or moreembodiments and certain variations and modifications, other variationsand modifications are within the scope of the invention, e.g., as may bewithin the skill and knowledge of those in the art, after understandingthe present disclosure. It is intended to obtain rights which includealternative embodiments to the extent permitted, including alternate,interchangeable and/or equivalent structures, functions, ranges or stepsto those claimed, whether or not such alternate, interchangeable and/orequivalent structures, functions, ranges or steps are disclosed herein,and without intending to publicly dedicate any patentable subjectmatter. All references cited herein are incorporated by reference intheir entirety.

What is claimed is:
 1. A compound of the formula:

wherein n is an integer from 0 to 4; each R¹ is independently selectedfrom the group consisting of alkyl, haloalkyl, halogen, nitro,heterocycloalkyl, cycloalkyl, optionally substituted heteroaryl,optionally substituted aryl, and —OR^(a), where each R^(a) isindependently selected from the group consisting of hydrogen, alkyl,heteroaryl, aryl and cycloalkyl; or two adjacent R¹ together with carbonatoms to which they are attached to form heterocycloalkyl; R² isselected from the group consisting of: (a) a moiety of the formula:

(b) a moiety of the formula:

(c) an optionally substituted aryl; and (d) an optionally substitutedheterocycloalkyl, wherein m is 1 or 2, X¹ is optionally substitutedheterocycloalkyl, —NR⁴R⁵, —NR^(b)SO₂R⁶, —NR^(b)C(O)R⁶, —NR^(b)SO₂NR⁴R⁵,or —NR^(b)CONR⁴R⁵; X² is O, NR^(c) or S; R³ and R^(3′) are eachindependently hydrogen or alkyl; each of R⁴ or R⁵ is independentlyhydrogen or alkyl, or R⁴ and R⁵ together with the nitrogen atom to whichthey are attached to form an optionally substituted heterocycloalkyl;each of R^(b) and R^(c) is independently hydrogen or alkyl; and R⁶ is—N(R^(d))₂, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl; provided that thecompound is not:N-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)propane-1-amine);1,1-diethyl-3-(2-(indolin-1yl)ethyl)urea;(N-(N,N-dimethylaminosulfonyl)-2-(indolin-1-yl)ethane-1-amine);4-(2-(indolin-1-yl)ethyl)morpholine;1-(2-(piperidin-1-yl)ethyl)indoline;N-(2-(indolin-1-yl)propyl)morpholine-4-sulfonamide;N-(2-(indolin-1-yl)propyl)piperidine-1-sulfonamide;4-fluoro-N-(2-(indolin-1-yl)propyl)benzenesulfonamide;4-fluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide;N-(2-(indolin-1-yl)ethyl)-4-methoxybenzenesulfonamide;3,4-difluoro-N-(2-(indolin-1yl)propyl)benzenesulfonamide;N-(2-(indolin-1-yl)propyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide;N-(2-(indolin-1-yl)ethyl)benzo[d][1,3]dioxole-5-sulfonamide;N-(2-(indolin-1-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide;N,N-diethyl-4-(2-(indolin-1-yl)-2-oxoethyl)piperazine-1-sulfonamide;1-(indolin-1-yl)-2-(4-(morpholinosulfonyl)piperazin-1-yl)ethan-1-one;1-(indolin-1-yl)-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethan-1-one;4-(3-indolin-1-yl)-3-oxopropyl)-N,N-dimethylpiperazine-1-sulfonamide;N,N-diethyl-4-(3-(indolin-1-yl)-3-oxopropyl)piperazine-1-sulfonamide;1-(indolin-1-yl)-3-(4-(morpholinosulfonyl)piperazin-1-yl)propan-1-one;1-(indolin-1-yl)-3-(4-(pyrimidin-2-yl)piperazin-1-yl)propan-1-one;2-(cycloheptylamino)-1-(indolin-1-yl)ethan-1-one; or3-(cycloheptylamino)-1-(indolin-1-yl)propan-1-one.
 2. The compound ofclaim 1 of the formula:

wherein n is 0 or 1; R⁶ is optionally substituted aryl; X¹ is —NR⁴R₅,—NR^(b)C(O)R⁶, —NR^(b)SO₂NR⁴R⁵ or —NR^(b)SO₂R⁶; R³ and R^(3′) are eachindependently hydrogen or alkyl; each of R⁴ and R⁵ is independentlyhydrogen or alkyl, or R⁴ and R⁵ together with the nitrogen atom to whichthey are attached to form an optionally substituted heterocycloalkyl;R^(b) is hydrogen or alkyl; and R⁶ is optionally substituted aryl oroptionally substituted heterocyclyl.
 3. The compound of claim 2, whereinX¹ is a —NR⁴R⁵, —NHC(O)R⁶, —NHSO₂NR⁴R⁵ or —NHSO₂R⁶; R³ and R^(3′) areeach independently hydrogen or methyl; R⁴ and R⁵ are alkyl, or R⁴ and R⁵together with the nitrogen atom to which they are attached to form anoptionally substituted piperazine ring; and R⁶ is optionally substitutedphenyl or optionally substituted pyrolidinyl.
 4. The compound of claim3, wherein n is 1; R¹ is 3-methoxyphenyl; and R⁴ and R⁵ are ethyl. 5.The compound of claim 3, wherein n is 0; R⁴ and R⁵ together with thenitrogen atom to which they are attached to form piperazine ringsubstituted with R⁷, wherein R⁷ is alkyl —SO₂R¹² or —SO₂NR⁸R⁹, whereinR⁸ and R⁹ are alkyl, R¹² is optionally substituted aryl; and R⁶ isphenyl or pyrolidinyl, wherein the phenyl is substituted with one ormore of halogen, haloalkyl, —O-haloalkyl,—O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl, cyano,-4-methoxyphenyl.
 6. The compound of claim 2, wherein R³ and R^(3′) arehydrogen.
 7. The compound of claim 2, wherein R³ is hydrogen and R^(3′)is methyl.
 8. The compound of claim 2, wherein R³ and R^(3′) are methyl.9. The compound of claim 1 of formula (Ib)

wherein X¹ is —NR⁴R⁵, —NHC(O)R⁶, —NHSO₂NR⁴R⁵ or —NHSO₂R⁶; R³ and R^(3′)are each independently hydrogen or methyl; when X¹ is —NR⁴R⁵, R⁴ and R⁵together with the nitrogen atom to which they are attached to form apiperazine ring, wherein the piperazine ring substituted with R⁷,wherein R⁷ is —SO₂R¹² or —SO₂NR⁸R⁹, wherein R⁸ and R⁹ are alkyl; and R¹²is phenyl substituted with halogen or —O-haloalkyl, when X¹ is —NHC(O)⁶,R⁶ is pyrrolidinyl, when X¹ is —NHSO₂NR⁴R⁶, wherein R⁵ and R⁵ are alkyl,and when X¹ is —NHSO₂R⁶, R⁶ is phenyl substituted with one or more of—O-alkyl, halogen, haloalkyl, —O-haloalkyl,—O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl or cyano.
 10. Thecompound of claim 9, wherein R⁸ and R⁹ are ethyl; R¹² is phenylsubstituted with fluoro or —O—CF_(3′), R⁴ and R⁵ are ethyl; and when X¹is —NHSO₂R⁶, R⁶ is phenyl substituted with one or more of —O—Me, fluoro,—CF₃, —O—CF₃, —O-(5-trifluoromethyl)pyridin-2-yl), —O-phenyl or cyano.11. The compound of claim 9, wherein X¹ is —NR⁴R⁵, —NHC(O)R⁶ or—NHSO₂R⁶; R³ is hydrogen and R^(3′) is hydrogen or methyl; when X¹ is—NR⁴R⁵, R⁴ and R⁵ together with the nitrogen atom to which they areattached to form a piperazine ring, wherein the piperazine ringsubstituted with R⁷, wherein R⁷ is —SO₂R¹² or —SO₂NR⁸R⁹, wherein R⁸ andR⁹ are alkyl; and R¹² is phenyl substituted with halogen or—O-haloalkyl. when X¹ is —NHC(O)R⁶, R⁶ is pyrrolidinyl, when X¹ is—NHSO₂R⁶, R⁶ is phenyl substituted with haloalkyl, —O-haloalkyl,—O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl or cyano.
 12. Thecompound of claim 11, wherein R⁸ and R⁹ are ethyl; R¹² is phenylsubstituted with fluoro or —O—CF₃; when X¹ is —NHSO₂R⁶, R⁶ is phenylsubstituted with —CF₃, —O—CF₃, —O-(5-(trifluoromethyl)pyridin-2-yl),—O-phenyl or cyano.
 13. The compound of claim 9, wherein X¹ is —NHSO₂R⁶;R³ and R^(3′) are methyl; R⁶ is phenyl substituted with one or more of—O-alkyl, halogen, haloalkyl, —O-haloalkyl,—O-(5-(trifluoromethyl)pyridin-2-yl), —O-phenyl or cyano.
 14. Thecompound of claim 13, wherein R⁶ is phenyl substituted with one or moreof —OMe, fluoro, —CF₃, —O—CF₃, —O-(5-(trifluoromethyl)pyridin-2-yl),—O-phenyl or cyano.
 15. The compound of claim 1, wherein the compoundis: N-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)ethane-1-amineN-(2-(indolin-1-yl)ethyl)pyrrolidine-1-sulfonamide1,1-diethyl-3-(2-(indolin-1-yl)propyl)ureaN-(N,N-dimethylaminosulfonyl)-2-(indolin-1-yl)propane-1-amineN-(2-(indolin-1-yl)propyl)pyrrolidine-1-sulfonamideN-(2-(indolin-1-yl)ethyl)-4-methylpiperazine-1-carboxamideN-(2-(indolin-1-yl)ethyl)morpholine-4-sulfonamideN-(2-(indolin-1-yl)ethyl)piperidine-1-sulfonamideN-(2-(indolin-1-yl)propyl)-4-methylpiperazine-1-carboxamideN-(2-(indolin-1-yl)propyl)pyrrolidine-1-carboxamideN-(2-indolin-1-yl)ethyl)pyrrolidine-1-carboxamide1-(indolin-1-yl)-2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethan-1-one1-(indolin-1-yl)-2-(4-(piperidin-1-ylsulfonyl)piperazin-1-yl)ethan-1-one4-(2-(indolin-1-yl)-2-oxoethyl)-N,N-dimethylpiperazine-1-sulfonamide1-(indolin-1-yl)-3-(4-(piperidin-1-ylsulfonyl)piperazin-1-yl)propan-1-oneN-(2-(indolin-1-yl)propyl)-2-(pyridin-4-yl)thiazole-4-carboxamideN-(2-(indolin-1-yl)propyl)-4-methoxybenzenesulfonamideN-(2-(5-(3-methoxyphenyl)indolin-1-yl)propyl)-N,N-diethyl-1-sulfonamideN-(2-(indolin-1-yl)propyl)-4-methylpiperazine-1-sulfonamideN-(2-(5-(3-methoxyphenyl)indolin-1-yl)propyl)-4-methylpiperazine-1-sulfonamideN-(N,N-diethylaminosulfonyl)-4-(indolin-1-yl)-phenyl-1-amineN-(2-(indolin-1-yl)propyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-2-(4-methoxyphenyl)thiazole-4-carboxamideN-(2-(indolin-1-yl)propyl)-2-phenylthiazole-4-carboxamideN-(2-(indolin-1-yl)propyl)-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide1-(2-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl)indolineN,N-diethyl-4-(2-(indolin-1-yl)ethyl)piperazine-1-sulfonamide1-(2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl)indolineN,N-diethyl-4-(2-(indolin-1-yl)ethyl)piperazine-1-carboxamide1-(2-(4-(2-fluorobenzyl)piperazin-1-yl)ethyl)indolineN-(2-(indolin-1-yl)propyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-phenoxybenzenesulfonamide4-cyano-N-(2-(indolin-1-yl)propyl)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-phenoxybenzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide3,4-difluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide4-cyano-N-(2-(indolin-1-yl)ethyl)benzenesulfonamideN-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)-2-methylpropane-1-amineN-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-phenoxybenzenesulfonamide4-fluoro-N-(2-(indolin-1-yl)-2-methylpropyl)benzenesulfonamide3,4-difluoro-N-(2-(indolin-1-yl)-2-methylpropyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-(methoxy)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethoxy)benzenesulfonamideor a pharmaceutically acceptable salt thereof.
 16. The compound of claim1, wherein the compound isN-(2-(indolin-1-yl)propyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)propyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-phenoxybenzenesulfonamideN-(2-(indolin-1-yl)ethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide3,4-difluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide4-cyano-N-(2-(indolin-1-yl)ethyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethyl)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-phenoxybenzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-methoxybenzenesulfonamideN-(2-(indolin-1-yl)-2-methylpropyl)-4-(trifluoromethoxy)benzenesulfonamideN-(2-(indolin-1-yl)ethyl)pyrrolidine-1-carboxamideN-(N,N-diethylaminosulfonyl)-2-(indolin-1-yl)-2-methylpropane-1-amine1-(2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl)indoline1-(2-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl)indolineN,N-diethyl-4-(2-(indolin-1-yl)ethyl)piperazine-1-sulfonamide or apharmaceutically acceptable salt thereof. The compound of claim 1,wherein the compound isN-(2-(indolin-1-yl)ethyl)-4-phenoxybenzenesulfonamideN-(2-indolin-1-yl)ethyl)4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzenesulfonamide3,4-difluoro-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide4-cyano-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide or apharmaceutically acceptable salt thereof. The compound of claim 1,wherein the compound is1-(2-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)ethyl)indolineN,N-diethyl-4-(2-(indolin-1-yl)ethyl)piperazine-1-sulfonamide.1-(2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)ethyl)indoline or apharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 20. A method for treating a clinical conditionassociated with fibrotic disorder, the method comprising administeringto a subject a therapeutically effective amount of the compound of claim1, or a pharmaceutically acceptable salt thereof, to treat the clinicalcondition associated with fibrotic disorder.